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Virology Journal

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This thematic series emphasizes advances and key discoveries in the animal origin, viral evolution, epidemiology, diagnostics and pathogenesis of different emerging and re-emerging coronaviruses.  Currently open for submissions -  Submit Here

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Top Reviewers of 2023

A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers, whose efforts often go unrecognized. Although final decisions are always editorial, they are greatly facilitated by the deeper technical knowledge, scientific insights, understanding of social consequences, and passion that reviewers bring to our deliberations. For these reasons, the Editors and staff of  Virology Journal  would like to publicly acknowledge our top peer reviewers of 2023.

Erna Geessien Kroon, PhD, Universidade Federal de Minas Gerais, Brazil Tanushree Dangi, PhD, Northwestern University, USA Vincent Wong, MD, The Chinese University of Hong Kong, Hong Kong Ming-Lun Yeh, PhD, Kaohsiung Medical University, Taiwan Tatsuo Kanda, PhD, Nihon University, Japan Pedro Augusto Alves, PhD, Instituto René Rachou, Brazil Sobia Idrees, PhD, Centenary Institute and the University of Technology Sydney, Australia Selvaraj Pavulraj, PhD, Louisiana State University, USA Sara Ebrahimi, PhD, Deakin University, Australia Yoon-Seok Chung, PhD, Korea Disease Control and Prevention Agency (KDCA), South Korea Cigdem Alkan Yirci, PhD, The University of Texas Medical Branch, USA Chen Guang, PhD, Duke-NUS Medical School, Singapore Yao-Chun Hsu, PhD, I-Shou University, Taiwan

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Unlocking influenza B: exploring molecular biology and reverse genetics for epidemic control and vaccine innovation

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Detection, characterization, and phylogenetic analysis of novel astroviruses from endemic Malagasy fruit bats

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Genetic diversity and cross-species transmissibility of bat-associated picornaviruses from Spain

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Detection and comparison of SARS-CoV-2 antibody produced in naturally infected patients and vaccinated individuals in Addis Ababa, Ethiopia: multicenter cross-sectional study

Authors: Chala Bashea, Addisu Gize, Tadesse Lejisa, Demiraw Bikila, Betselot Zerihun, Feyissa Challa, Daniel Melese, Alganesh Gebreyohanns, Kasahun Gorems, Solomon Ali, Gadissa Bedada Hundie, Habteyes Hailu Tola and Wondewosen Tsegaye

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Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

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Coronavirus envelope protein: current knowledge

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False negative rate of COVID-19 PCR testing: a discordant testing analysis

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Adverse effects of COVID-19 vaccines and measures to prevent them

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The effect of temperature on persistence of SARS-CoV-2 on common surfaces

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Virology Journal is an open access, peer reviewed journal that considers articles on all aspects of virology, including research on the viruses of animals, plants and microbes. The journal welcomes basic research as well as pre-clinical and clinical studies of novel diagnostic tools, vaccines and anti-viral therapies.

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Clinical Virology : Fred Kibenge, University of Prince Edward Island, Canada  Emerging viruses : Tom Geisbert,  University of Texas Medical Branch, USA Hepatitis viruses : Wan-Long Chuang,  Kaohsiung Medical University, Taiwan Herpes viruses : Tony Cunningham,  The Westmead Institute for Medical Research, Australia Influenza viruses : Hualan Chen,  Chinese Academy of Agricultural Sciences, China Negative-strand RNA viruses : John Barr,  University of Leeds, UK Other viruses : Erna Geessien Kroon,  Universidade Federal de Minas Gerais, Brazil Plant viruses : Supriya Chakraborty,  Jawaharlal Nehru University, India Positive-strand RNA viruses : Jaquelline Germano de Oliveira,  Fundação Oswaldo Cruz - Fiocruz, Brazil  Public health :  Kin On Kwok,  The Chinese University of Hong Kong Retroviruses : Aguinaldo Pinto, Universidade Federal de Santa Catarina, Brazil Veterinary DNA viruses : Walid Azab,  Freie Universität Berlin, Germany Veterinary RNA viruses : James Weger-Lucarelli,  Virginia Tech, USA Viruses of microbes : Joana Azeredo,  University of Minho, Portugal

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Alan McLachlan, Co-Editor-in-Chief

Alan McLachlan is a molecular geneticist and hepadnavirologist. He currently serves as a Professor in the Department of Microbiology and Immunology, University of Illinois Chicago, USA. His interests are focused on hepatitis viruses, primarily on hepatitis B virus (HBV) and its relationships to liver physiology.  His research is currently directed toward understanding the relationships between HBV transcription and viral biosynthesis using both cell culture and animal models.  His long-term goals include the identification of cellular gene products as targets for the development of small molecular weight antiviral compounds which, in combination with current nuceot(s)ide analog therapeutics, will resolve chronic HBV infections.

Leo Poon, Co-Editor-in-Chief

Leo Poon is a molecular virologist. He currently serves as a Professor in the School of Public Health, The University of Hong Kong and as a co-director of HKU-Pasteur Research Pole. He has strong interests in emerging viruses, including coronavirus and influenza virus. He researches on different aspects of these viruses, ranging from basic virology to clinical diagnosis. His ultimate goal is to use scientific findings to inform public health policy. Over the years, he has published about 290 peer-reviewed articles. Thus far, his work has been cited over 41,000 times and he has an H-index of 95 (Web of Science).

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• Virology, transmission...

Virology, transmission, and pathogenesis of SARS-CoV-2

Read our latest coverage of the coronavirus outbreak.

• Related content
• Peer review
• Muge Cevik , clinical lecturer 1 2 ,
• Krutika Kuppalli , assistant professor 3 ,
• Jason Kindrachuk , assistant professor of virology 4 ,
• Malik Peiris , professor of virology 5
• 1 Division of Infection and Global Health Research, School of Medicine, University of St Andrews, St Andrews, UK
• 2 Specialist Virology Laboratory, Royal Infirmary of Edinburgh, Edinburgh, UK and Regional Infectious Diseases Unit, Western General Hospital, Edinburgh, UK
• 3 Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC, USA
• 4 Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada
• 5 School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
• Correspondence to M Cevik mc349{at}st-andrews.ac.uk

What you need to know

SARS-CoV-2 is genetically similar to SARS-CoV-1, but characteristics of SARS-CoV-2—eg, structural differences in its surface proteins and viral load kinetics—may help explain its enhanced rate of transmission

In the respiratory tract, peak SARS-CoV-2 load is observed at the time of symptom onset or in the first week of illness, with subsequent decline thereafter, indicating the highest infectiousness potential just before or within the first five days of symptom onset

Reverse transcription polymerase chain reaction (RT-PCR) tests can detect viral SARS-CoV-2 RNA in the upper respiratory tract for a mean of 17 days; however, detection of viral RNA does not necessarily equate to infectiousness, and viral culture from PCR positive upper respiratory tract samples has been rarely positive beyond nine days of illness

Symptomatic and pre-symptomatic transmission (1-2 days before symptom onset), is likely to play a greater role in the spread of SARS-CoV-2 than asymptomatic transmission

A wide range of virus-neutralising antibodies have been reported, and emerging evidence suggests that these may correlate with severity of illness but wane over time

Since the emergence of SARS-CoV-2 in December 2019, there has been an unparalleled global effort to characterise the virus and the clinical course of disease. Coronavirus disease 2019 (covid-19), caused by SARS-CoV-2, follows a biphasic pattern of illness that likely results from the combination of an early viral response phase and an inflammatory second phase. Most clinical presentations are mild, and the typical pattern of covid-19 more resembles an influenza-like illness—which includes fever, cough, malaise, myalgia, headache, and taste and smell disturbance—rather than severe pneumonia (although emerging evidence about long term consequences is yet to be understood in detail). 1 In this review, we provide a broad update on the emerging understanding of SARS-CoV-2 pathophysiology, including virology, transmission dynamics, and the immune response to the virus. Any of the mechanisms and assumptions discussed in the article and in our understanding of covid-19 may be revised as further evidence emerges.

What we know about the virus

SARS-CoV-2 is an enveloped β-coronavirus, with a genetic sequence very similar to SARS-CoV-1 (80%) and bat coronavirus RaTG13 (96.2%). 2 The viral envelope is coated by spike (S) glycoprotein, envelope (E), and membrane (M) proteins ( fig 1 ). Host cell binding and entry are mediated by the S protein. The first step in infection is virus binding to a host cell through its target receptor. The S1 sub-unit of the S protein contains the receptor binding domain that binds to the peptidase domain of angiotensin-converting enzyme 2 (ACE 2). In SARS-CoV-2 the S2 sub-unit is highly preserved and is considered a potential antiviral target. The virus structure and replication cycle are described in figure 1 .

(1) The virus binds to ACE 2 as the host target cell receptor in synergy with the host’s transmembrane serine protease 2 (cell surface protein), which is principally expressed in the airway epithelial cells and vascular endothelial cells. This leads to membrane fusion and releases the viral genome into the host cytoplasm (2). Stages (3-7) show the remaining steps of viral replication, leading to viral assembly, maturation, and virus release

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Coronaviruses have the capacity for proofreading during replication, and therefore mutation rates are lower than in other RNA viruses. As SARS-CoV-2 has spread globally it has, like other viruses, accumulated some mutations in the viral genome, which contains geographic signatures. Researchers have examined these mutations to study virus characterisation and understand epidemiology and transmission patterns. In general, the mutations have not been attributed to phenotypic changes affecting viral transmissibility or pathogenicity. The G614 variant in the S protein has been postulated to increase infectivity and transmissibility of the virus. 3 Higher viral loads were reported in clinical samples with virus containing G614 than previously circulating variant D614, although no association was made with severity of illness as measured by hospitalisation outcomes. 3 These findings have yet to be confirmed with regards to natural infection.

Why is SARS-CoV-2 more infectious than SARS-CoV-1?

SARS-CoV-2 has a higher reproductive number (R 0 ) than SARS-CoV-1, indicating much more efficient spread. 1 Several characteristics of SARS-CoV-2 may help explain this enhanced transmission. While both SARS-CoV-1 and SARS-CoV-2 preferentially interact with the angiotensin-converting enzyme 2 (ACE 2) receptor, SARS-CoV-2 has structural differences in its surface proteins that enable stronger binding to the ACE 2 receptor 4 and greater efficiency at invading host cells. 1 SARS-CoV-2 also has greater affinity (or bonding) for the upper respiratory tract and conjunctiva, 5 thus can infect the upper respiratory tract and can conduct airways more easily. 6

Viral load dynamics and duration of infectiousness

Viral load kinetics could also explain some of the differences between SARS-CoV-2 and SARS-CoV-1. In the respiratory tract, peak SARS-CoV-2 load is observed at the time of symptom onset or in the first week of illness, with subsequent decline thereafter, which indicates the highest infectiousness potential just before or within the first five days of symptom onset ( fig 2 ). 7 In contrast, in SARS-CoV-1 the highest viral loads were detected in the upper respiratory tract in the second week of illness, which explains its minimal contagiousness in the first week after symptom onset, enabling early case detection in the community. 7

After the initial exposure, patients typically develop symptoms within 5-6 days (incubation period). SARS-CoV-2 generates a diverse range of clinical manifestations, ranging from mild infection to severe disease accompanied by high mortality. In patients with mild infection, initial host immune response is capable of controlling the infection. In severe disease, excessive immune response leads to organ damage, intensive care admission, or death. The viral load peaks in the first week of infection, declines thereafter gradually, while the antibody response gradually increases and is often detectable by day 14 (figure adapted with permission from https://www.sciencedirect.com/science/article/pii/S009286742030475X ; https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30230-7/fulltext )

Quantitative reverse transcription polymerase chain reaction (qRT-PCR) technology can detect viral SARS-CoV-2 RNA in the upper respiratory tract for a mean of 17 days (maximum 83 days) after symptom onset. 7 However, detection of viral RNA by qRT-PCR does not necessarily equate to infectiousness, and viral culture from PCR positive upper respiratory tract samples has been rarely positive beyond nine days of illness. 5 This corresponds to what is known about transmission based on contact tracing studies, which is that transmission capacity is maximal in the first week of illness, and that transmission after this period has not been documented. 8 Severely ill or immune-compromised patients may have relatively prolonged virus shedding, and some patients may have intermittent RNA shedding; however, low level results close to the detection limit may not constitute infectious viral particles. While asymptomatic individuals (those with no symptoms throughout the infection) can transmit the infection, their relative degree of infectiousness seems to be limited. 9 10 11 People with mild symptoms (paucisymptomatic) and those whose symptom have not yet appeared still carry large amounts of virus in the upper respiratory tract, which might contribute to the easy and rapid spread of SARS-CoV-2. 7 Symptomatic and pre-symptomatic transmission (one to two days before symptom onset) is likely to play a greater role in the spread of SARS-CoV-2. 10 12 A combination of preventive measures, such as physical distancing and testing, tracing, and self-isolation, continue to be needed.

Route of transmission and transmission dynamics

Like other coronaviruses, the primary mechanism of transmission of SARS-CoV-2 is via infected respiratory droplets, with viral infection occurring by direct or indirect contact with nasal, conjunctival, or oral mucosa, when respiratory particles are inhaled or deposited on these mucous membranes. 6 Target host receptors are found mainly in the human respiratory tract epithelium, including the oropharynx and upper airway. The conjunctiva and gastrointestinal tracts are also susceptible to infection and may serve as transmission portals. 6

Transmission risk depends on factors such as contact pattern, environment, infectiousness of the host, and socioeconomic factors, as described elsewhere. 12 Most transmission occurs through close range contact (such as 15 minutes face to face and within 2 m), 13 and spread is especially efficient within households and through gatherings of family and friends. 12 Household secondary attack rates (the proportion of susceptible individuals who become infected within a group of susceptible contacts with a primary case) ranges from 4% to 35%. 12 Sleeping in the same room as, or being a spouse of an infected individual increases the risk of infection, but isolation of the infected person away from the family is related to lower risk of infection. 12 Other activities identified as high risk include dining in close proximity with the infected person, sharing food, and taking part in group activities 12 The risk of infection substantially increases in enclosed environments compared with outdoor settings. 12 For example, a systematic review of transmission clusters found that most superspreading events occurred indoors. 11 Aerosol transmission can still factor during prolonged stay in crowded, poorly ventilated indoor settings (meaning transmission could occur at a distance >2 m). 12 14 15 16 17

The role of faecal shedding in SARS-CoV-2 transmission and the extent of fomite (through inanimate surfaces) transmission also remain to be fully understood. Both SARS-CoV-2 and SARS-CoV-1 remain viable for many days on smooth surfaces (stainless steel, plastic, glass) and at lower temperature and humidity (eg, air conditioned environments). 18 19 Thus, transferring infection from contaminated surfaces to the mucosa of eyes, nose, and mouth via unwashed hands is a possible route of transmission. This route of transmission may contribute especially in facilities with communal areas, with increased likelihood of environmental contamination. However, both SARS-CoV-1 and SARS-CoV-2 are readily inactivated by commonly used disinfectants, emphasising the potential value of surface cleaning and handwashing. SARS-CoV-2 RNA has been found in stool samples and RNA shedding often persists for longer than in respiratory samples 7 ; however, virus isolation has rarely been successful from the stool. 5 7 No published reports describe faecal-oral transmission. In SARS-CoV-1, faecal-oral transmission was not considered to occur in most circumstances; but, one explosive outbreak was attributed to aerosolisation and spread of the virus across an apartment block via a faulty sewage system. 20 It remains to be seen if similar transmission may occur with SARS-CoV-2.

Pathogenesis

Viral entry and interaction with target cells.

SARS-CoV-2 binds to ACE 2, the host target cell receptor. 1 Active replication and release of the virus in the lung cells lead to non-specific symptoms such as fever, myalgia, headache, and respiratory symptoms. 1 In an experimental hamster model, the virus causes transient damage to the cells in the olfactory epithelium, leading to olfactory dysfunction, which may explain temporary loss of taste and smell commonly seen in covid-19. 21 The distribution of ACE 2 receptors in different tissues may explain the sites of infection and patient symptoms. For example, the ACE 2 receptor is found on the epithelium of other organs such as the intestine and endothelial cells in the kidney and blood vessels, which may explain gastrointestinal symptoms and cardiovascular complications. 22 Lymphocytic endotheliitis has been observed in postmortem pathology examination of the lung, heart, kidney, and liver as well as liver cell necrosis and myocardial infarction in patients who died of covid-19. 1 23 These findings indicate that the virus directly affects many organs, as was seen in SARS-CoV-1 and influenzae.

Much remains unknown. Are the pathological changes in the respiratory tract or endothelial dysfunction the result of direct viral infection, cytokine dysregulation, coagulopathy, or are they multifactorial? And does direct viral invasion or coagulopathy directly contribute to some of the ischaemic complications such as ischaemic infarcts? These and more, will require further work to elucidate.

Immune response and disease spectrum ( figure 2 )

After viral entry, the initial inflammatory response attracts virus-specific T cells to the site of infection, where the infected cells are eliminated before the virus spreads, leading to recovery in most people. 24 In patients who develop severe disease, SARS-CoV-2 elicits an aberrant host immune response. 24 25 For example, postmortem histology of lung tissues of patients who died of covid-19 have confirmed the inflammatory nature of the injury, with features of bilateral diffuse alveolar damage, hyaline-membrane formation, interstitial mononuclear inflammatory infiltrates, and desquamation consistent with acute respiratory distress syndrome (ARDS), and is similar to the lung pathology seen in severe Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). 26 27 A distinctive feature of covid-19 is the presence of mucus plugs with fibrinous exudate in the respiratory tract, which may explain the severity of covid-19 even in young adults. 28 This is potentially caused by the overproduction of pro-inflammatory cytokines that accumulate in the lungs, eventually damaging the lung parenchyma. 24

Some patients also experience septic shock and multi-organ dysfunction. 24 For example, the cardiovascular system is often involved early in covid-19 disease and is reflected in the release of highly sensitive troponin and natriuretic peptides. 29 Consistent with the clinical context of coagulopathy, focal intra-alveolar haemorrhage and presence of platelet-fibrin thrombi in small arterial vessels is also seen. 27 Cytokines normally mediate and regulate immunity, inflammation, and haematopoiesis; however, further exacerbation of immune reaction and accumulation of cytokines in other organs in some patients may cause extensive tissue damage, or a cytokine release syndrome (cytokine storm), resulting in capillary leak, thrombus formation, and organ dysfunction. 24 30

Mechanisms underlying the diverse clinical outcomes

Clinical outcomes are influenced by host factors such as older age, male sex, and underlying medical conditions, 1 as well as factors related to the virus (such as viral load kinetics), host-immune response, and potential cross-reactive immune memory from previous exposure to seasonal coronaviruses ( box 1 ).

Risk factors associated with the development of severe disease, admission to intensive care unit, and mortality

Underlying condition.

Hypertension

Cardiovascular disease

Chronic obstructive pulmonary disease

Presentation

Higher fever (≥39°C on admission)

Dyspnoea on admission

Higher qSOFA score

Laboratory markers

Neutrophilia/lymphopenia

Raised lactate and lactate dehydrogenase

Raised C reactive protein

Raised ferritin

Raised IL-6

Raised ACE2

D-dimer >1 μg/mL

Sex-related differences in immune response have been reported, revealing that men had higher plasma innate immune cytokines and chemokines at baseline than women. 31 In contrast, women had notably more robust T cell activation than men, and among male participants T cell activation declined with age, which was sustained among female patients. These findings suggest that adaptive immune response may be important in defining the clinical outcome as older age and male sex is associated with increased risk of severe disease and mortality.

Increased levels of pro-inflammatory cytokines correlate with severe pneumonia and increased ground glass opacities within the lungs. 30 32 In people with severe illness, increased plasma concentrations of inflammatory cytokines and biomarkers were observed compared with people with non-severe illness. 30 33 34

Emerging evidence suggests a correlation between viral dynamics, the severity of illness, and disease outcome. 7 Longitudinal characteristics of immune response show a correlation between the severity of illness, viral load, and IFN- α, IFN-γ, and TNF-α response. 34 In the same study many interferons, cytokines, and chemokines were elevated early in disease for patients who had severe disease and higher viral loads. This emphasises that viral load may drive these cytokines and the possible pathological roles associated with the host defence factors. This is in keeping with the pathogenesis of influenza, SARS, and MERS whereby prolonged viral shedding was also associated with severity of illness. 7 35

Given the substantial role of the immune response in determining clinical outcomes, several immunosuppressive therapies aimed at limiting immune-mediated damage are currently in various phases of development ( table 1 ).

Therapeutics currently under investigation

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Immune response to the virus and its role in protection

Covid-19 leads to an antibody response to a range of viral proteins, but the spike (S) protein and nucleocapsid are those most often used in serological diagnosis. Few antibodies are detectable in the first four days of illness, but patients progressively develop them, with most achieving a detectable response after four weeks. 36 A wide range of virus-neutralising antibodies have been reported, and emerging evidence suggests that these may correlate with severity but wane over time. 37 The duration and protectivity of antibody and T cell responses remain to be defined through studies with longer follow-up. CD-4 T cell responses to endemic human coronaviruses appear to manifest cross-reactivity with SARS-CoV-2, but their role in protection remains unclear. 38

Unanswered questions

Further understanding of the pathogenesis for SARS-CoV-2 will be vital in developing therapeutics, vaccines, and supportive care modalities in the treatment of covid-19. More data are needed to understand the determinants of healthy versus dysfunctional response and immune markers for protection and the severity of disease. Neutralising antibodies are potential correlates of protection, but other protective antibody mechanisms may exist. Similarly, the protective role of T cell immunity and duration of both antibody and T cell responses and the correlates of protection need to be defined. In addition, we need optimal testing systems and technologies to support and inform early detection and clinical management of infection. Greater understanding is needed regarding the long term consequences following acute illness and multisystem inflammatory disease, especially in children.

Education into practice

How would you describe SARS-CoV-2 transmission routes and ways to prevent infection?

How would you describe to a patient why cough, anosmia, and fever occur in covid-19?

Questions for future research

What is the role of the cytokine storm and how could it inform the development of therapeutics, vaccines, and supportive care modalities?

What is the window period when patients are most infectious?

Why do some patients develop severe disease while others, especially children, remain mildly symptomatic or do not develop symptoms?

What are the determinants of healthy versus dysfunctional response, and the biomarkers to define immune correlates of protection and disease severity for the effective triage of patients?

What is the protective role of T cell immunity and duration of both antibody and T cell responses, and how would you define the correlates of protection?

How patients were involved in the creation of this article

No patients were directly involved in the creation of this article.

How this article was created

We searched PubMed from 2000 to 18 September 2020, limited to publications in English. Our search strategy used a combination of key words including “COVID-19,” “SARS-CoV-2,” “SARS”, “MERS,” “Coronavirus,” “Novel Coronavirus,” “Pathogenesis,” “Transmission,” “Cytokine Release,” “immune response,” “antibody response.” These sources were supplemented with systematic reviews. We also reviewed technical documents produced by the Centers for Disease Control and Prevention and World Health Organization technical documents.

Author contributions: MC, KK, JK, MP drafted the first and subsequent versions of the manuscript and all authors provided critical feedback and contributed to the manuscript.

Competing interests The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none.

Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests

Provenance and peer review: commissioned; externally peer reviewed.

This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

• Bamford CGG ,
• Fischer WM ,
• Gnanakaran S ,
• Sheffield COVID-19 Genomics Group
• Corbett KS ,
• Corman VM ,
• Guggemos W ,
• Cheung MC ,
• Perera RAPM ,
• Cheng H-Y ,
• Taiwan COVID-19 Outbreak Investigation Team
• Meyerowitz E ,
• Richterman A ,
• Nergiz AI ,
• Maraolo AE ,
• Buitrago-Garcia D ,
• Egli-Gany D ,
• Counotte MJ ,
• ↵ European Centre for Disease Prevention and Control. Surveillance definitions for COVID-19. 2020. https://www.ecdc.europa.eu/en/covid-19/surveillance/surveillance-definitions .
• Klompas M ,
• ↵ Centers for Disease Control and Prevention. How COVID-19 spreads. 2020. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/how-covid-spreads.html
• ↵ Centers for Disease Control and Prevention. Scientific brief: SARS-CoV-2 and potential airborne transmission. 2020. https://www.cdc.gov/coronavirus/2019-ncov/more/scientific-brief-sars-cov-2.html
• Perera MRA ,
• van Doremalen N ,
• Bushmaker T ,
• Morris DH ,
• Monteil V ,
• Flammer AJ ,
• Steiger P ,
• Mangalmurti N ,
• Blanco-Melo D ,
• Nilsson-Payant BE ,
• Carsana L ,
• Sonzogni A ,
• ↵ Takahashi T, Ellingson MK, Wong P, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature 2020. https://pubmed.ncbi.nlm.nih.gov/32846427/
• Yale IMPACT Team
• CAP-China Network
• Perera RA ,
• Merrick B ,
• Grifoni A ,
• Weiskopf D ,
• Ramirez SI ,

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Neurological impact of respiratory viruses: insights into glial cell responses in the central nervous system.

1. Introduction

2. glial cells in the central nervous system, 2.1. microglia, 2.2. astrocytes, 3. respiratory viruses and the glial cells of the cns, 3.1. human respiratory syncytial virus, 3.2. severe acute respiratory syndrome coronavirus 2, 3.3. influenza virus, 3.4. human parvoviruses.

4. Conclusions

Author contributions, data availability statement, conflicts of interest.

• Jessen, K.R. Glial cells. Int. J. Biochem. Cell Biol. 2004 , 36 , 1861–1867. [ Google Scholar ] [ CrossRef ]
• Allen, N.J.; Lyons, D.A. Glia as architects of central nervous system formation and function. Science 2018 , 362 , 181–185. [ Google Scholar ] [ CrossRef ]
• Xu, S.; Lu, J.; Shao, A.; Zhang, J.H.; Zhang, J. Glial Cells: Role of the Immune Response in Ischemic Stroke. Front. Immunol. 2020 , 11 , 294. [ Google Scholar ] [ CrossRef ]
• Bohmwald, K.; Gálvez, N.M.S.; Ríos, M.; Kalergis, A.M. Neurologic alterations due to respiratory virus infections. Front. Cell. Neurosci. 2018 , 12 , 386. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Heegaard, E.D.; Brown, K.E. Human parvovirus B19. Clin. Microbiol. Rev. 2002 , 15 , 485–505. [ Google Scholar ] [ CrossRef ]
• Boncristiani, H.F.; Criado, M.F.; Arruda, E. Respiratory Viruses. In Encyclopedia of Microbiology , 3rd ed.; Academic Press: Cambridge, MA, USA, 2009; pp. 500–518. [ Google Scholar ] [ CrossRef ]
• Qiu, J.; Söderlund-Venermo, M.; Young, N.S. Human parvoviruses. Clin. Microbiol. Rev. 2017 , 30 , 43–113. [ Google Scholar ] [ PubMed ]
• Bhattacharya, S.; Agarwal, S.; Shrimali, N.M.; Guchhait, P. Interplay between hypoxia and inflammation contributes to the progression and severity of respiratory viral diseases. Mol. Aspects Med. 2021 , 81 , 101000. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Bohmwald, K.; Andrade, C.A.; Mora, V.P.; Muñoz, J.T.; Ramírez, R.; Rojas, M.F.; Kalergis, A.M. Neurotrophin Signaling Impairment by Viral Infections in the Central Nervous System. Int. J. Mol. Sci. 2022 , 23 , 5817. [ Google Scholar ] [ CrossRef ]
• Watanabe, T. Acute encephalitis and encephalopathy associated with human parvovirus B19 infection in children. World J. Clin. Pediatr. 2015 , 4 , 126. [ Google Scholar ] [ CrossRef ]
• Bohmwald, K.; Andrade, C.A.; Kalergis, A.M. Contribution of pro-inflammatory molecules induced by respiratory virus infections to neurological disorders. Pharmaceuticals 2021 , 14 , 340. [ Google Scholar ] [ CrossRef ]
• Jäkel, S.; Dimou, L. Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation. Front. Cell. Neurosci. 2017 , 11 , 24. [ Google Scholar ] [ CrossRef ]
• Antel, J.P.; Becher, B.; Ludwin, S.K.; Prat, A.; Quintana, F.J. Glial Cells as Regulators of Neuroimmune Interactions in the Central Nervous System. J. Immunol. 2020 , 204 , 251–255. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Nayak, D.; Roth, T.L.; McGavern, D.B. Microglia Development and function. Annu. Rev. Immunol. 2014 , 32 , 367. [ Google Scholar ] [ CrossRef ]
• Spiteri, A.G.; Wishart, C.L.; Pamphlett, R.; Locatelli, G.; King, N.J.C. Microglia and monocytes in inflammatory CNS disease: Integrating phenotype and function. Acta Neuropathol. 2022 , 143 , 179–224. [ Google Scholar ] [ CrossRef ]
• Borst, K.; Dumas, A.A.; Prinz, M. Microglia: Immune and non-immune functions. Immunity 2021 , 54 , 2194–2208. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Xu, P.; Yu, Y.; Wu, P. Role of microglia in brain development after viral infection. Front. Cell Dev. Biol. 2024 , 12 , 1340308. [ Google Scholar ] [ CrossRef ]
• Yang, I.; Han, S.J.; Kaur, G.; Crane, C.; Parsa, A.T. The role of microglia in central nervous system immunity and glioma immunology. J. Clin. Neurosci. 2010 , 17 , 6–10. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Fiebich, B.L.; Batista, C.R.A.; Saliba, S.W.; Yousif, N.M.; de Oliveira, A.C.P. Role of microglia TLRs in neurodegeneration. Front. Cell. Neurosci. 2018 , 12 , 329. [ Google Scholar ] [ CrossRef ]
• Olson, J.K.; Miller, S.D. Microglia Initiate Central Nervous System Innate and Adaptive Immune Responses through Multiple TLRs. J. Immunol. 2004 , 173 , 3916–3924. [ Google Scholar ] [ CrossRef ]
• Guo, S.; Wang, H.; Yin, Y. Microglia Polarization From M1 to M2 in Neurodegenerative Diseases. Front. Aging Neurosci. 2022 , 14 , 815347. [ Google Scholar ] [ CrossRef ]
• Tremblay, M.E.; Madore, C.; Bordeleau, M.; Tian, L.; Verkhratsky, A. Neuropathobiology of COVID-19: The Role for Glia. Front. Cell. Neurosci. 2020 , 14 , 592214. [ Google Scholar ] [ CrossRef ]
• Ransohoff, R.M. A polarizing question: Do M1 and M2 microglia exist. Nat. Neurosci. 2016 , 19 , 987–991. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Giovannoni, F.; Quintana, F.J. The Role of Astrocytes in CNS Inflammation. Trends Immunol. 2020 , 41 , 805–819. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sofroniew, M.V.; Vinters, H.V. Astrocytes: Biology and pathology. Acta Neuropathol. 2009 , 119 , 7–35. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Deneen, B.; Akdemir, E.S.; Huang, A.Y.S. Astrocytogenesis: Where, when, and how. F1000Research 2020 , 9 , 233. [ Google Scholar ] [ CrossRef ]
• Filous, A.R.; Silver, J. Targeting astrocytes in CNS injury and disease: A translational research approach. Prog. Neurobiol. 2016 , 144 , 173–187. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Lundgaard, I.; Osório, M.J.; Kress, B.T.; Sanggaard, S.; Nedergaard, M. White matter astrocytes in health and disease. Neuroscience 2014 , 276 , 161–173. [ Google Scholar ] [ CrossRef ]
• Dong, Y.; Benveniste, E.N. Immune function of astrocytes. Glia 2001 , 36 , 180–190. [ Google Scholar ] [ CrossRef ]
• Villablanca, C.; Vidal, R.; Gonzalez-Billault, C. Are cytoskeleton changes observed in astrocytes functionally linked to aging? Brain Res. Bull. 2023 , 196 , 59–67. [ Google Scholar ] [ CrossRef ]
• Lawrence, J.M.; Schardien, K.; Wigdahl, B.; Nonnemacher, M.R. Roles of neuropathology-associated reactive astrocytes: A systematic review. Acta Neuropathol. Commun. 2023 , 11 , 42. [ Google Scholar ] [ CrossRef ]
• Oberheim, N.A.; Goldman, S.A.; Nedergaard, M. Heterogeneity of Astrocytic Form and Function. Methods Mol. Biol. 2012 , 814 , 23. [ Google Scholar ] [ CrossRef ]
• Siracusa, R.; Fusco, R.; Cuzzocrea, S. Astrocytes: Role and functions in brain pathologies. Front. Pharmacol. 2019 , 10 , 1114. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Ding, Z.B.; Song, L.J.; Wang, Q.; Kumar, G.; Yan, Y.Q.; Ma, C.G. Astrocytes: A double-edged sword in neurodegenerative diseases. Neural Regen. Res. 2021 , 16 , 1702–1710. [ Google Scholar ] [ PubMed ]
• Rodgers, K.R.; Lin, Y.; Langan, T.J.; Iwakura, Y.; Chou, R.C. Innate Immune Functions of Astrocytes are Dependent Upon Tumor Necrosis Factor-Alpha. Sci. Rep. 2020 , 10 , 7047. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Zimmerman, R.K.; Balasubramani, G.K.; D’Agostino, H.E.A.; Clarke, L.; Yassin, M.; Middleton, D.B.; Silveira, F.P.; Wheeler, N.D.; Landis, J.; Peterson, A.; et al. Population-based hospitalization burden estimates for respiratory viruses, 2015–2019. Influenza Other Respi. Viruses 2022 , 16 , 1133–1140. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Bohmwald, K.; Andrade, C.A.; Gálvez, N.M.S.; Mora, V.P.; Muñoz, J.T.; Kalergis, A.M. The Causes and Long-Term Consequences of Viral Encephalitis. Front. Cell. Neurosci. 2021 , 15 , 755875. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Griffiths, C.; Drews, S.J.; Marchant, D.J. Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment. Am. Soc. Microbiol. 2017 , 30 , 277–319. [ Google Scholar ]
• Andrade, C.A.; Kalergis, A.M.; Bohmwald, K. Potential Neurocognitive Symptoms Due to Respiratory Syncytial Virus Infection. Pathogens 2022 , 11 , 47. [ Google Scholar ]
• Chen, L.; Cai, J.; Zhang, J.; Tang, Y.; Chen, J.; Xiong, S.; Li, Y.; Zhang, H.; Liu, Z.; Li, M.; et al. Respiratory syncytial virus co-opts hypoxia-inducible factor-1α-mediated glycolysis to favor the production of infectious virus. mBio 2023 , 14 , e0211023. [ Google Scholar ]
• Haeberle, H.A.; Dürrstein, C.; Rosenberger, P.; Hosakote, Y.M.; Kuhlicke, J.; Kempf, V.A.J.; Garofalo, R.P.; Eitzschig, H.K. Oxygen-independent stabilization of hypoxia inducible factor (HIF)-1 during RSV infection. PLoS ONE 2008 , 3 , 14–16. [ Google Scholar ] [ CrossRef ]
• Zhuang, X.; Gallo, G.; Sharma, P.; Ha, J.; Magri, A.; Borrmann, H.; Harris, J.M.; Tsukuda, S.; Bentley, E.; Kirby, A.; et al. Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression. iScience 2024 , 27 , 108763. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Lee, S.J.; Kim, J.M.; Keum, H.R.; Kim, S.W.; Baek, H.S.; Byun, J.C.; Kim, Y.K.; Kim, S.; Lee, J.M. Seasonal Trends in the Prevalence and Incidence of Viral Encephalitis in Korea (2015–2019). J. Clin. Med. 2023 , 12 , 2003. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Saravanos, G.L.; King, C.L.; Deng, L.; Dinsmore, N.; Ramos, I.; Takashima, M.; Crawford, N.; Clark, J.E.; Dale, R.C.; Jones, C.A.; et al. Respiratory Syncytial Virus–Associated Neurologic Complications in Children: A Systematic Review and Aggregated Case Series. J. Pediatr. 2021 , 239 , 39–49.e9. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• He, Y.; Wang, Z.; Wei, J.; Yang, Z.; Ren, L.; Deng, Y.; Chen, S.; Zang, N.; Liu, E. Exploring Key Genes and Mechanisms in Respiratory Syncytial Virus-Infected BALB/c Mice via Multi-Organ Expression Profiles. Front. Cell. Infect. Microbiol. 2022 , 12 , 858305. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Bohmwald, K.; Soto, J.A.; Andrade-Parra, C.; Fernández-Fierro, A.; Espinoza, J.A.; Ríos, M.; Eugenin, E.A.; González, P.A.; Opazo, M.C.; Riedel, C.A.; et al. Lung pathology due to hRSV infection impairs blood–brain barrier permeability enabling astrocyte infection and a long-lasting inflammation in the CNS. Brain. Behav. Immun. 2021 , 91 , 159–171. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Morichi, S.; Kawashima, H.; Ioi, H.; Yamanaka, G.; Kashiwagi, Y.; Hoshika, A.; Nakayama, T.; Watanabe, Y. Classification of acute encephalopathy in respiratory syncytial virus infection. J. Infect. Chemother. 2011 , 17 , 776–781. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Feng, Z.; Xu, L.; Xie, Z. Receptors for Respiratory Syncytial Virus Infection and Host Factors Regulating the Life Cycle of Respiratory Syncytial Virus. Front. Cell. Infect. Microbiol. 2022 , 12 , 858629. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Ozawa, D.; Nakamura, T.; Koike, M.; Hirano, K.; Miki, Y.; Beppu, M. Shuttling protein nucleolin is a microglia receptor for amyloid beta peptide 1-42. Biol. Pharm. Bull. 2013 , 36 , 1587–1593. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Müller, N. The role of intercellular adhesion molecule-1 in the pathogenesis of psychiatric disorders. Front. Pharmacol. 2019 , 10 , 1251. [ Google Scholar ] [ CrossRef ]
• Vartak-Sharma, N.; Ghorpade, A. Astrocyte elevated gene-1 regulates astrocyte responses to neural injury: Implications for reactive astrogliosis and neurodegeneration. J. Neuroinflamm. 2012 , 9 , 195. [ Google Scholar ] [ CrossRef ]
• Meucci, O.; Fatatis, A.; Simen, A.A.; Miller, R.J. Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc. Natl. Acad. Sci. USA 2000 , 97 , 8075–8080. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Romano, R.; Bucci, C. Role of EGFR in the Nervous System. Cells 2020 , 9 , 1887. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Qu, W.S.; Tian, D.S.; Guo, Z.B.; Fang, J.; Zhang, Q.; Yu, Z.Y.; Xie, M.J.; Zhang, H.Q.; Lü, J.G.; Wang, W. Inhibition of EGFR/MAPK signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury. J. Neuroinflamm. 2012 , 9 , 178. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Tselnicker, I.F.; Boisvert, M.M.; Allen, N.J. The role of neuronal versus astrocyte-derived heparan sulfate proteoglycans in brain development and injury. Biochem. Soc. Trans. 2014 , 42 , 1263–1269. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• O’Callaghan, P.; Zhang, X.; Li, J.P. Heparan Sulfate Proteoglycans as Relays of Neuroinflammation. J. Histochem. Cytochem. 2018 , 66 , 305–319. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Mao, Y.; Bajinka, O.; Tang, Z.; Qiu, X.; Tan, Y. Lung–brain axis: Metabolomics and pathological changes in lungs and brain of respiratory syncytial virus-infected mice. J. Med. Virol. 2022 , 94 , 5885–5893. [ Google Scholar ] [ CrossRef ]
• Bajinka, O.; Tang, Z.; Mao, Y.; Qiu, X.; Darboe, A.; Tan, Y. Respiratory syncytial virus infection disrupts pulmonary microbiota to induce microglia phenotype shift. J. Med. Virol. 2023 , 95 , e28976. [ Google Scholar ] [ CrossRef ]
• Zhang, X.Y.; Zhang, X.C.; Yu, H.Y.; Wang, Y.; Chen, J.; Wang, Y.; Yu, L.; Zhu, G.X.; Cao, X.J.; Huang, S.H. Respiratory syncytial virus infection of microglia exacerbates SH-SY5Y neuronal cell injury by inducing the secretion of inflammatory cytokines: A Transwell in vitro study. Iran. J. Basic Med. Sci. 2021 , 24 , 213–221. [ Google Scholar ] [ CrossRef ]
• Gusev, E.; Sarapultsev, A.; Solomatina, L.; Chereshnev, V. SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19. Int. J. Mol. Sci. 2022 , 23 , 1716. [ Google Scholar ] [ CrossRef ]
• Pal, M.; Berhanu, G.; Desalegn, C.; Kandi, V. Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2): An Update. Cureus 2020 , 12 , e7423. [ Google Scholar ] [ CrossRef ]
• Lamers, M.M.; Haagmans, B.L. SARS-CoV-2 pathogenesis. Nat. Rev. Microbiol. 2022 , 20 , 270–284. [ Google Scholar ] [ CrossRef ]
• Jeong, G.U.; Lyu, J.; Kim, K.-D.; Chung, Y.C.; Yoon, G.Y.; Lee, S.; Hwang, I.; Shin, W.-H.; Ko, J.; Lee, J.-Y.; et al. SARS-CoV-2 Infection of Microglia Elicits Proinflammatory Activation and Apoptotic Cell Death. Microbiol. Spectr. 2022 , 10 , e0109122. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Samudyata; Oliveira, A.O.; Malwade, S.; Rufino de Sousa, N.; Goparaju, S.K.; Gracias, J.; Orhan, F.; Steponaviciute, L.; Schalling, M.; Sheridan, S.D.; et al. SARS-CoV-2 promotes microglial synapse elimination in human brain organoids. Mol. Psychiatry 2022 , 27 , 3939–3950. [ Google Scholar ] [ CrossRef ]
• Jahani, M.; Dokaneheifard, S.; Mansouri, K. Hypoxia: A key feature of COVID-19 launching activation of HIF-1 and cytokine storm. J. Inflamm. 2020 , 17 , 33. [ Google Scholar ] [ CrossRef ]
• Luo, Z.; Tian, M.; Yang, G.; Tan, Q.; Chen, Y.; Li, G.; Zhang, Q.; Li, Y.; Wan, P.; Wu, J. Hypoxia signaling in human health and diseases: Implications and prospects for therapeutics. Signal Transduct. Target. Ther. 2022 , 7 , 218. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Rutkai, I.; Mayer, M.G.; Hellmers, L.M.; Ning, B.; Huang, Z.; Monjure, C.J.; Coyne, C.; Silvestri, R.; Golden, N.; Hensley, K.; et al. Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates. Nat. Commun. 2022 , 13 , 1745. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Adingupu, D.D.; Soroush, A.; Hansen, A.; Twomey, R.; Dunn, J.F. Brain hypoxia, neurocognitive impairment, and quality of life in people post-COVID-19. J. Neurol. 2023 , 270 , 3303–3314. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Leng, A.; Shah, M.; Ahmad, S.A.; Premraj, L.; Wildi, K.; Li Bassi, G.; Pardo, C.A.; Choi, A.; Cho, S.M. Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics. Cells 2023 , 12 , 816. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Zalpoor, H.; Akbari, A.; Samei, A.; Forghaniesfidvajani, R.; Kamali, M.; Afzalnia, A.; Manshouri, S.; Heidari, F.; Pornour, M.; Khoshmirsafa, M.; et al. The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: Inflammasome and JaK inhibitors as potential promising therapies. Cell. Mol. Biol. Lett. 2022 , 27 , 10. [ Google Scholar ] [ CrossRef ]
• Steardo, L.; Steardo, L.; Scuderi, C. Astrocytes and the Psychiatric Sequelae of COVID-19: What We Learned from the Pandemic. Neurochem. Res. 2023 , 48 , 1015–1025. [ Google Scholar ] [ CrossRef ]
• Awogbindin, I.O.; Ben-Azu, B.; Olusola, B.A.; Akinluyi, E.T.; Adeniyi, P.A.; Di Paolo, T.; Tremblay, M.È. Microglial Implications in SARS-CoV-2 Infection and COVID-19: Lessons From Viral RNA Neurotropism and Possible Relevance to Parkinson’s Disease. Front. Cell. Neurosci. 2021 , 15 , 670298. [ Google Scholar ] [ CrossRef ]
• Yao, C.; Liu, X.; Tang, Y.; Wang, C.; Duan, C.; Liu, X.; Chen, M.; Zhou, Y.; Tang, E.; Xiang, Y.; et al. Lipopolysaccharide induces inflammatory microglial activation through CD147-mediated matrix metalloproteinase expression. Environ. Sci. Pollut. Res. 2023 , 30 , 35352–35365. [ Google Scholar ] [ CrossRef ]
• Huang, Y.; Happonen, K.E.; Burrola, P.G.; O’Connor, C.; Hah, N.; Huang, L.; Nimmerjahn, A.; Lemke, G. Microglia use TAM receptors to detect and engulf amyloid β plaques. Nat. Immunol. 2021 , 22 , 586–594. [ Google Scholar ] [ CrossRef ]
• Dey, R.; Bishayi, B. Microglial Inflammatory Responses to SARS-CoV-2 Infection: A Comprehensive Review. Cell. Mol. Neurobiol. 2024 , 44 , 2. [ Google Scholar ] [ CrossRef ]
• Zhang, Y.; Chen, X.; Jia, L.; Zhang, Y. Potential mechanism of SARS-CoV-2-associated central and peripheral nervous system impairment. Acta Neurol. Scand. 2022 , 146 , 225–236. [ Google Scholar ] [ CrossRef ]
• Ferraro, E.; Germanò, M.; Mollace, R.; Mollace, V.; Malara, N. HIF-1, the Warburg Effect, and Macrophage/Microglia Polarization Potential Role in COVID-19 Pathogenesis. Oxid. Med. Cell. Longev. 2021 , 2021 , 8841911. [ Google Scholar ] [ CrossRef ]
• Olivarria, G.M.; Cheng, Y.; Furman, S.; Pachow, C.; Hohsfield, L.A.; Smith-Geater, C.; Miramontes, R.; Wu, J.; Burns, M.S.; Tsourmas, K.I.; et al. Microglia Do Not Restrict SARS-CoV-2 Replication following Infection of the Central Nervous System of K18-Human ACE2 Transgenic Mice. J. Virol. 2022 , 96 , e0196921. [ Google Scholar ] [ CrossRef ]
• Savelieff, M.G.; Feldman, E.L.; Stino, A.M. Neurological sequela and disruption of neuron-glia homeostasis in SARS-CoV-2 infection. Neurobiol. Dis. 2022 , 168 , 293. [ Google Scholar ] [ CrossRef ]
• Albornoz, E.A.; Amarilla, A.A.; Modhiran, N.; Parker, S.; Li, X.X.; Wijesundara, D.K.; Aguado, J.; Zamora, A.P.; McMillan, C.L.D.; Liang, B.; et al. SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein. Mol. Psychiatry 2022 , 28 , 2878–2893. [ Google Scholar ] [ CrossRef ]
• Garber, C.; Soung, A.; Vollmer, L.L.; Kanmogne, M.; Last, A.; Brown, J.; Klein, R.S. T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from neuropathogenic flaviviruses. Nat. Neurosci. 2019 , 22 , 1276. [ Google Scholar ] [ CrossRef ]
• Su, W.; Ju, J.; Gu, M.; Wang, X.; Liu, S.; Yu, J.; Mu, D. SARS-CoV-2 envelope protein triggers depression-like behaviors and dysosmia via TLR2-mediated neuroinflammation in mice. J. Neuroinflamm. 2023 , 20 , 110. [ Google Scholar ] [ CrossRef ]
• Chen, Y.; Yang, W.; Chen, F.; Cui, L. COVID-19 and cognitive impairment: Neuroinvasive and blood–brain barrier dysfunction. J. Neuroinflamm. 2022 , 19 , 222. [ Google Scholar ] [ CrossRef ]
• Beckman, D.; Bonillas, A.; Diniz, G.B.; Ott, S.; Roh, J.W.; Elizaldi, S.R.; Schmidt, B.A.; Sammak, R.L.; Van Rompay, K.K.A.; Iyer, S.S.; et al. SARS-CoV-2 infects neurons and induces neuroinflammation in a non-human primate model of COVID-19. Cell Rep. 2022 , 41 , 111573. [ Google Scholar ] [ CrossRef ]
• Kempuraj, D.; Aenlle, K.K.; Cohen, J.; Mathew, A.; Isler, D.; Pangeni, R.P.; Nathanson, L.; Theoharides, T.C.; Klimas, N.G. COVID-19 and Long COVID: Disruption of the Neurovascular Unit, Blood-Brain Barrier, and Tight Junctions. Neuroscientist 2023 , 11 , 10738584231194927. [ Google Scholar ] [ CrossRef ]
• Zhang, L.; Zhou, L.; Bao, L.; Liu, J.; Zhu, H.; Lv, Q.; Liu, R.; Chen, W.; Tong, W.; Wei, Q.; et al. SARS-CoV-2 crosses the blood–brain barrier accompanied with basement membrane disruption without tight junctions alteration. Signal Transduct. Target. Ther. 2021 , 6 , 337. [ Google Scholar ] [ CrossRef ]
• Malik, J.R.; Acharya, A.; Avedissian, S.N.; Byrareddy, S.N.; Fletcher, C.V.; Podany, A.T.; Dyavar, S.R. ACE-2, TMPRSS2, and Neuropilin-1 Receptor Expression on Human Brain Astrocytes and Pericytes and SARS-CoV-2 Infection Kinetics. Int. J. Mol. Sci. 2023 , 24 , 8622. [ Google Scholar ] [ CrossRef ]
• Kong, W.; Montano, M.; Corley, M.J.; Helmy, E.; Kobayashi, H.; Kinisu, M.; Suryawanshi, R.; Luo, X.; Royer, L.A.; Roan, N.R.; et al. Neuropilin-1 Mediates SARS-CoV-2 Infection of Astrocytes in Brain Organoids, Inducing Inflammation Leading to Dysfunction and Death of Neurons. MBio 2022 , 13 , e0230822. [ Google Scholar ] [ CrossRef ]
• Crunfli, F.; Carregari, V.C.; Veras, F.P.; Silva, L.S.; Henrique, M.; Mayara, E.; Firmino, S.; Paiva, I.M. Morphological, cellular, and molecular basis of brain infection in COVID-19 patients. Proc. Natl. Acad. Sci. USA 2022 , 119 , e2200960119. [ Google Scholar ] [ CrossRef ]
• Patrizz, A.; Doran, S.J.; Chauhan, A.; Ahnstedt, H.; Roy-O’Reilly, M.; Lai, Y.J.; Weston, G.; Tarabishy, S.; Patel, A.R.; Verma, R.; et al. EMMPRIN/CD147 plays a detrimental role in clinical and experimental ischemic stroke. Aging 2020 , 12 , 5121–5139. [ Google Scholar ] [ CrossRef ]
• Meertens, L.; Labeau, A.; Dejarnac, O.; Cipriani, S.; Sinigaglia, L.; Bonnet-Madin, L.; Le Charpentier, T.; Hafirassou, M.L.; Zamborlini, A.; Cao-Lormeau, V.M.; et al. Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses. Cell Rep. 2017 , 18 , 324–333. [ Google Scholar ] [ CrossRef ]
• Mifsud, E.J.; Kuba, M.; Barr, I.G. Innate immune responses to influenza virus infections in the upper respiratory tract. Viruses 2021 , 13 , 2090. [ Google Scholar ] [ CrossRef ]
• Ekstrand, J.J. Neurologic Complications of Influenza. Semin. Pediatr. Neurol. 2012 , 19 , 96–100. [ Google Scholar ] [ CrossRef ]
• Guo, X.; Zhu, Z.; Zhang, W.; Meng, X.; Zhu, Y.; Han, P.; Zhou, X.; Hu, Y.; Wang, R. Nuclear translocation of HIF-1α induced by influenza A (H1N1) infection is critical to the production of proinflammatory cytokines. Emerg. Microbes Infect. 2017 , 6 , e39. [ Google Scholar ] [ CrossRef ]
• Zhao, C.; Chen, J.; Cheng, L.; Xu, K.; Yang, Y.; Su, X. Deficiency of HIF-1α enhances influenza A virus replication by promoting autophagy in alveolar type II epithelial cells. Emerg. Microbes Infect. 2020 , 9 , 691–706. [ Google Scholar ] [ CrossRef ]
• Fugate, J.E.; Lam, E.M.; Rabinstein, A.A.; Wijdicks, E.F.M. Acute hemorrhagic leukoencephalitis and hypoxic brain injury associated with H1N1 influenza. Arch. Neurol. 2010 , 67 , 756–758. [ Google Scholar ] [ CrossRef ]
• Wang, K.Y.; Singer, H.S.; Crain, B.; Gujar, S.; Lin, D.D.M. Hypoxic-ischemic encephalopathy mimicking acute necrotizing encephalopathy. Pediatr. Neurol. 2015 , 52 , 110–114. [ Google Scholar ] [ CrossRef ]
• Ding, X.M.; Wang, Y.F.; Lyu, Y.; Zou, Y.; Wang, X.; Ruan, S.M.; Wu, W.H.; Liu, H.; Sun, Y.; Zhang, R.L.; et al. The effect of influenza A (H1N1) pdm09 virus infection on cytokine production and gene expression in BV2 microglial cells. Virus Res. 2022 , 312 , 198716. [ Google Scholar ] [ CrossRef ]
• Sieben, C.; Sezgin, E.; Eggeling, C.; Manley, S. Influenza a viruses use multivalent sialic acid clusters for cell binding and receptor activation. PLoS Pathog. 2020 , 16 , e1008656. [ Google Scholar ] [ CrossRef ]
• Düsedau, H.P.; Steffen, J.; Figueiredo, C.A.; Boehme, J.D.; Schultz, K.; Erck, C.; Korte, M.; Faber-Zuschratter, H.; Smalla, K.H.; Dieterich, D.; et al. Influenza A Virus (H1N1) Infection Induces Microglial Activation and Temporal Dysbalance in Glutamatergic Synaptic Transmission. mBio 2021 , 12 , e0177621. [ Google Scholar ] [ CrossRef ]
• Pei, X.D.; Zhai, Y.F.; Zhang, H.H. Influenza virus H1N1 induced apoptosis of mouse astrocytes and the effect on protein expression. Asian Pac. J. Trop. Med. 2014 , 7 , 572–575. [ Google Scholar ] [ CrossRef ]
• Ng, Y.P.; Lee, S.M.Y.; Cheung, T.K.W.; Nicholls, J.M.; Peiris, J.S.M.; Ip, N.Y. Avian influenza H5N1 virus induces cytopathy and proinflammatory cytokine responses in human astrocytic and neuronal cell lines. Neuroscience 2010 , 168 , 613–623. [ Google Scholar ] [ CrossRef ]
• Ng, Y.P.; Yip, T.F.; Peiris, J.S.M.; Ip, N.Y.; Lee, S.M.Y. Avian influenza A H7N9 virus infects human astrocytes and neuronal cells and induces inflammatory immune responses. J. Neurovirol. 2018 , 24 , 752–760. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Jiang, H.; Qiu, Q.; Zhou, Y.; Zhang, Y.; Xu, W.; Cui, A.; Li, X. The epidemiological and genetic characteristics of human parvovirus B19 in patients with febrile rash illnesses in China. Sci. Rep. 2023 , 13 , 15913. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Dittmer, F.P.; de Guimarães, C.M.; Peixoto, A.B.; Pontes, K.F.M.; Bonasoni, M.P.; Tonni, G.; Araujo Júnior, E. Parvovirus B19 Infection and Pregnancy: Review of the Current Knowledge. J. Pers. Med. 2024 , 14 , 139. [ Google Scholar ] [ CrossRef ]
• Zou, Q.; Chen, P.; Chen, J.; Chen, D.; Xia, H.; Chen, L.; Feng, H.; Feng, L. Multisystem Involvement Induced by Human Parvovirus B19 Infection in a Non-immunosuppressed Adult: A Case Report. Front. Med. 2022 , 9 , 808205. [ Google Scholar ] [ CrossRef ]
• Pichon, M.; Labois, C.; Tardy-Guidollet, V.; Mallet, D.; Casalegno, J.S.; Billaud, G.; Lina, B.; Gaucherand, P.; Mekki, Y. Optimized nested PCR enhances biological diagnosis and phylogenetic analysis of human parvovirus B19 infections. Arch. Virol. 2019 , 164 , 2775–2781. [ Google Scholar ] [ CrossRef ]
• Pillet, S.; Le Guyader, N.; Hofer, T.; Nguyenkhac, F.; Koken, M.; Aubin, J.T.; Fichelson, S.; Gassmann, M.; Morinet, F. Hypoxia enhances human B19 erythrovirus gene expression in primary erythroid cells. Virology 2004 , 327 , 1–7. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Xu, M.; Leskinen, K.; Gritti, T.; Groma, V.; Arola, J.; Lepistö, A.; Sipponen, T.; Saavalainen, P.; Söderlund-Venermo, M. Prevalence, Cell Tropism, and Clinical Impact of Human Parvovirus Persistence in Adenomatous, Cancerous, Inflamed, and Healthy Intestinal Mucosa. Front. Microbiol. 2022 , 13 , 914181. [ Google Scholar ] [ CrossRef ]
• Barah, F.; Whiteside, S.; Batista, S.; Morris, J. Neurological aspects of human parvovirus B19 infection: A systematic review. Rev. Med. Virol. 2014 , 24 , 154–168. [ Google Scholar ] [ CrossRef ]
• Pattabiraman, C.; Prasad, P.; Sudarshan, S.; George, A.K.; Sreenivas, D.; Rasheed, R.; Ghosh, A.; Pal, A.; Hameed, S.K.S.; Bandyopadhyay, B.; et al. Identification and Genomic Characterization of Parvovirus B19V Genotype 3 Viruses from Cases of Meningoencephalitis in West Bengal, India. Microbiol. Spectr. 2022 , 10 , e0225121. [ Google Scholar ] [ CrossRef ]
• Skuja, S.; Vilmane, A.; Svirskis, S.; Groma, V.; Murovska, M. Evidence of human parvovirus B19 infection in the post-mortem brain tissue of the elderly. Viruses 2018 , 10 , 8–12. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Isumi, H.; Nunoue, T.; Nishida, A.; Takashima, S. Fetal brain infection with human parvovirus B19. Pediatr. Neurol. 1999 , 21 , 661–663. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Manning, A.; Willey, S.J.; Bell, J.E.; Simmonds, P. Comparison of tissue distribution, persistence, and molecular epidemiology of parvovirus B19 and novel human parvoviruses PARV4 and human bocavirus. J. Infect. Dis. 2007 , 195 , 1345–1352. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Hobbs, J.A. Detection of adeno-associated virus 2 and parvovirus B19 in the human dorsolateral prefrontal cortex. J. Neurovirol. 2006 , 12 , 190–199. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Trapani, S.; Caporizzi, A.; Ricci, S.; Indolfi, G. Human Bocavirus in Childhood: A True Respiratory Pathogen or a “Passenger” Virus? A Comprehensive Review. Microorganisms 2023 , 11 , 1243. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Yu, J.M.; Chen, Q.Q.; Hao, Y.X.; Yu, T.; Zeng, S.Z.; Wu, X.B.; Zhang, B.; Duan, Z.J. Identification of human bocaviruses in the cerebrospinal fluid of children hospitalized with encephalitis in China. J. Clin. Virol. 2013 , 57 , 374–377. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Mitui, M.T.; Shahnawaz Bin Tabib, S.M.; Matsumoto, T.; Khanam, W.; Ahmed, S.; Mori, D.; Akhter, N.; Yamada, K.; Kabir, L.; Nishizono, A.; et al. Detection of human bocavirus in the cerebrospinal fluid of children with encephalitis. Clin. Infect. Dis. 2012 , 54 , 964–967. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Ergul, A.B.; Altug, U.; Aydin, K.; Guven, A.S.; Altuner Torun, Y. Acute necrotizing encephalopathy causing human bocavirus. Neuroradiol. J. 2017 , 30 , 164–167. [ Google Scholar ] [ CrossRef ]
• Akturk, H.; Sidotlessk, G.; Salman, N.; Sutcu, M.; Tatli, B.; Akcay Ciblak, M.; Bulent Erol, O.; Hancerli Torun, S.; Citak, A.; Somer, A. Atypical presentation of human bocavirus: Severe respiratory tract infection complicated with encephalopathy. J. Med. Virol. 2015 , 87 , 1831–1838. [ Google Scholar ] [ CrossRef ]
• Vilmane, A.; Terentjeva, A.; Tamosiunas, P.L.; Suna, N.; Suna, I.; Petraityte-burneikiene, R.; Murovska, M.; Rasa-dzelzkaleja, S.; Nora- Krukle, Z. Human parvoviruses may affect the development and clinical course of meningitis and meningoencephalitis. Brain Sci. 2020 , 10 , 339. [ Google Scholar ] [ CrossRef ]
• Thapa, R.R.; Plentz, A.; Edinger, M.; Wolff, D.; Angstwurm, K.; Söderlund-Venermo, M. Human bocavirus 1 respiratory tract reactivations or reinfections in two adults, contributing to neurological deficits and death. Access Microbiol. 2021 , 3 , 237. [ Google Scholar ] [ CrossRef ]
• Mohammadi, M. HBoV-1: Virus structure, genomic features, life cycle, pathogenesis, epidemiology, diagnosis and clinical manifestations. Front. Cell. Infect. Microbiol. 2023 , 13 , 1198127. [ Google Scholar ] [ CrossRef ]
• Agungpriyono, D.R.; Uchida, K.; Tabaru, H.; Yamaguchi, R.; Tateyama, S. Subacute massive necrotizing myocarditis by canine parvovirus type 2 infection with diffuse leukoencephalomalacia in a puppy. Vet. Pathol. 1999 , 36 , 77–80. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Shao, L.; Shen, W.; Wang, S.; Qiu, J. Recent Advances in Molecular Biology of Human Bocavirus 1 and Its Applications. Front. Microbiol. 2021 , 12 , 696604. [ Google Scholar ] [ CrossRef ]
• Luo, Y.; Qiu, J. Human parvovirus B19: A mechanistic overview of infection and DNA replication. Future Virol. 2015 , 10 , 155–167. [ Google Scholar ] [ CrossRef ]
• Ning, K.; Zou, W.; Xu, P.; Cheng, F.; Zhang, E.Y.; Zhang-Chen, A.; Kleiboeker, S.; Qiu, J. Identification of AXL as a co-receptor for human parvovirus B19 infection of human erythroid progenitors. Sci. Adv. 2023 , 9 , ade0869. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Piewbang, C.; Wardhani, S.W.; Dankaona, W.; Lacharoje, S.; Chai-In, P.; Yostawonkul, J.; Chanseanroj, J.; Boonrungsiman, S.; Kasantikul, T.; Poovorawan, Y.; et al. Canine bocavirus-2 infection and its possible association with encephalopathy in domestic dogs. PLoS ONE 2021 , 16 , 0255425. [ Google Scholar ] [ CrossRef ]
• Schildgen, O.; Schildgen, V. The Role of the Human Bocavirus (HBoV) in Respiratory Infections. Adv. Tech. Diagn. Microbiol. 2018 , 2 , 281. [ Google Scholar ] [ CrossRef ]

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Mora, V.P.; Kalergis, A.M.; Bohmwald, K. Neurological Impact of Respiratory Viruses: Insights into Glial Cell Responses in the Central Nervous System. Microorganisms 2024 , 12 , 1713. https://doi.org/10.3390/microorganisms12081713

Mora VP, Kalergis AM, Bohmwald K. Neurological Impact of Respiratory Viruses: Insights into Glial Cell Responses in the Central Nervous System. Microorganisms . 2024; 12(8):1713. https://doi.org/10.3390/microorganisms12081713

Mora, Valentina P., Alexis M. Kalergis, and Karen Bohmwald. 2024. "Neurological Impact of Respiratory Viruses: Insights into Glial Cell Responses in the Central Nervous System" Microorganisms 12, no. 8: 1713. https://doi.org/10.3390/microorganisms12081713

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A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence

Affiliations.

• 1 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
• 2 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
• 3 National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, USA.
• 4 Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
• 5 Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
• 6 Cystic Fibrosis Center, Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
• 7 Institute for Research in Biomedicine, Bellinzona Institute of Microbiology, Zurich, Switzerland.
• 8 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
• 9 Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
• PMID: 26552008
• PMCID: PMC4797993
• DOI: 10.1038/nm.3985
• Corrigendum: A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Menachery VD, Yount BL Jr, Debbink K, Agnihothram S, Gralinski LE, Plante JA, Graham RL, Scobey T, Ge XY, Donaldson EF, Randell SH, Lanzavecchia A, Marasco WA, Shi ZL, Baric RS. Menachery VD, et al. Nat Med. 2016 Apr;22(4):446. doi: 10.1038/nm0416-446d. Nat Med. 2016. PMID: 27050591 Free PMC article. No abstract available.
• Author Correction: A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Menachery VD, Yount BL Jr, Debbink K, Agnihothram S, Gralinski LE, Plante JA, Graham RL, Scobey T, Ge XY, Donaldson EF, Randell SH, Lanzavecchia A, Marasco WA, Shi ZL, Baric RS. Menachery VD, et al. Nat Med. 2020 Jul;26(7):1146. doi: 10.1038/s41591-020-0924-2. Nat Med. 2020. PMID: 32661400 Free PMC article.

The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS)-CoV underscores the threat of cross-species transmission events leading to outbreaks in humans. Here we examine the disease potential of a SARS-like virus, SHC014-CoV, which is currently circulating in Chinese horseshoe bat populations. Using the SARS-CoV reverse genetics system, we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone. The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein. On the basis of these findings, we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo. Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.

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Conflict of interest statement

The authors declare no competing financial interests.

Figure 1. SARS-like viruses replicate in human…

Figure 1. SARS-like viruses replicate in human airway cells and produce in vivo pathogenesis.

Figure 2. SARS-CoV monoclonal antibodies have marginal…

Figure 2. SARS-CoV monoclonal antibodies have marginal efficacy against SARS-like CoVs.

Figure 3. Full-length SHC014-CoV replicates in human…

Figure 3. Full-length SHC014-CoV replicates in human airways but lacks the virulence of epidemic SARS-CoV.

Figure 4. Emergence paradigms for coronaviruses.

Coronavirus…

Coronavirus strains are maintained in quasi-species pools circulating in…

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• Review Article
• Published: 16 July 2019

Evolution and ecology of plant viruses

• Pierre Lefeuvre   ORCID: orcid.org/0000-0003-2645-8098 1 ,
• Darren P. Martin 2 ,
• Santiago F. Elena 3 , 4 ,
• Dionne N. Shepherd 5 ,
• Philippe Roumagnac   ORCID: orcid.org/0000-0001-5002-6039 6 , 7 &
• Arvind Varsani   ORCID: orcid.org/0000-0003-4111-2415 8 , 9  

Nature Reviews Microbiology volume  17 ,  pages 632–644 ( 2019 ) Cite this article

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• Microbial ecology
• Viral evolution
• Viral vectors
• Virus–host interactions

The discovery of the first non-cellular infectious agent, later determined to be tobacco mosaic virus, paved the way for the field of virology. In the ensuing decades, research focused on discovering and eliminating viral threats to plant and animal health. However, recent conceptual and methodological revolutions have made it clear that viruses are not merely agents of destruction but essential components of global ecosystems. As plants make up over 80% of the biomass on Earth, plant viruses likely have a larger impact on ecosystem stability and function than viruses of other kingdoms. Besides preventing overgrowth of genetically homogeneous plant populations such as crop plants, some plant viruses might also promote the adaptation of their hosts to changing environments. However, estimates of the extent and frequencies of such mutualistic interactions remain controversial. In this Review, we focus on the origins of plant viruses and the evolution of interactions between these viruses and both their hosts and transmission vectors. We also identify currently unknown aspects of plant virus ecology and evolution that are of practical importance and that should be resolvable in the near future through viral metagenomics.

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Edwards, R. A. & Rohwer, F. Viral metagenomics. Nat. Rev. Microbiol. 3 , 504–510 (2005).

CAS   PubMed   Google Scholar  

Greninger, A. L. A decade of RNA virus metagenomics is (not) enough. Virus Res. 244 , 218–229 (2018).

Koonin, E. V. & Dolja, V. V. Metaviromics: a tectonic shift in understanding virus evolution. Virus Res. 246 , A1–A3 (2018). This review highlights how our understanding of virology is changing as a consequence of advances in metagenomics .

Suttle, C. A. Viruses: unlocking the greatest biodiversity on Earth. Genome 56 , 542–544 (2013).

PubMed   Google Scholar  

Gregory, A. C. et al. Marine DNA viral macro- and microdiversity from pole to pole. Cell 177 , 1109–1123 (2019). This study provides the most comprehensive inventory of marine viral diversity to date .

CAS   PubMed   PubMed Central   Google Scholar  

Morris, J. L. et al. The timescale of early land plant evolution. Proc. Natl Acad. Sci. USA 115 , E2274–E2283 (2018).

Mushegian, A., Shipunov, A. & Elena, S. F. Changes in the composition of the RNA virome mark evolutionary transitions in green plants. BMC Biol. 14 , 68 (2016).

PubMed   PubMed Central   Google Scholar  

Bernardo, P. et al. Geometagenomics illuminates the impact of agriculture on the distribution and prevalence of plant viruses at the ecosystem scale. ISME J. 12 , 173–184 (2018). This article is a viromics study of agro-ecological interfaces that demonstrates the impacts of agriculture on the diversity and prevalence of plant-associated viruses .

Muthukumar, V. et al. Non-cultivated plants of the Tallgrass Prairie Preserve of northeastern Oklahoma frequently contain virus-like sequences in particulate fractions. Virus Res. 141 , 169–173 (2009).

Koonin, E. V., Dolja, V. V. & Krupovic, M. Origins and evolution of viruses of eukaryotes: the ultimate modularity. Virology 479–480 , 2–25 (2015).

Nasir, A. & Caetano-Anolles, G. A phylogenomic data-driven exploration of viral origins and evolution. Sci. Adv. 1 , e1500527 (2015).

Dolja, V. V. & Koonin, E. V. Common origins and host-dependent diversity of plant and animal viromes. Curr. Opin. Virol. 1 , 322–331 (2011).

Wolf, Y. I. et al. Origins and evolution of the global RNA virome. mBio 9 , e02329–18 (2018). This study yields new insights relating to the evolution of RNA viruses in light of novel RNA viruses that have recently been discovered using metagenomics techniques .

Volk, M., Gibbs, A. J. & Suttle, C. A. Metagenomes of a freshwater charavirus from British Columbia provide a window into ancient lineages of viruses. Viruses 11 , 299 (2019).

Google Scholar  

Krupovic, M. & Koonin, E. V. Multiple origins of viral capsid proteins from cellular ancestors. Proc. Natl Acad. Sci. USA 114 , E2401–E2410 (2017).

Dolja, V. V. & Koonin, E. V. Metagenomics reshapes the concepts of RNA virus evolution by revealing extensive horizontal virus transfer. Virus Res. 244 , 36–52 (2018).

Roossinck, M. J. Evolutionary and ecological links between plant and fungal viruses. New Phytol. 221 , 86–92 (2019). This review describes our current knowledge of mycoviruses and their evolutionary relationships with plant viruses .

Vieira, P. & Nemchinov, L. G. A novel species of RNA virus associated with root lesion nematode Pratylenchus penetrans . J. Gen. Virol. 100 , 704–708 (2019).

Hollings, M. Viruses associated with a die-back disease of cultivated mushroom. Nature 196 , 962–965 (1962).

Pearson, M. N., Beever, R. E., Boine, B. & Arthur, K. Mycoviruses of filamentous fungi and their relevance to plant pathology. Mol. Plant Pathol. 10 , 115–128 (2009).

Mu, F. et al. Virome characterization of a collection of S. sclerotiorum from Australia. Front. Microbiol. 8 , 2540 (2017).

Marzano, S. L. & Domier, L. L. Novel mycoviruses discovered from metatranscriptomics survey of soybean phyllosphere phytobiomes. Virus Res. 213 , 332–342 (2016).

Gilbert, K., Holcomb, E. E., Allscheid, R. L. & Carrington, J. Discovery of new mycoviral genomes within publicly available fungal transcriptomic datasets. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/510404v1 (2019).

Marzano, S. L. et al. Identification of diverse mycoviruses through metatranscriptomics characterization of the viromes of five major fungal plant pathogens. J. Virol. 90 , 6846–6863 (2016).

Frank, A. C. & Wolfe, K. H. Evolutionary capture of viral and plasmid DNA by yeast nuclear chromosomes. Eukaryot. Cell 8 , 1521–1531 (2009).

Taylor, D. J. & Bruenn, J. The evolution of novel fungal genes from non-retroviral RNA viruses. BMC Biol. 7 , 88 (2009).

Hillman, B. I. & Cai, G. The family Narnaviridae: simplest of RNA viruses. Adv. Virus Res. 86 , 149–176 (2013).

Nerva, L. et al. Biological and molecular characterization of Chenopodium quinoa mitovirus 1 reveals a distinct small RNA response compared to those of cytoplasmic RNA viruses. J. Virol. 93 , e01998–18 (2019).

Rastgou, M. et al. Molecular characterization of the plant virus genus Ourmiavirus and evidence of inter-kingdom reassortment of viral genome segments as its possible route of origin. J. Gen. Virol. 90 , 2525–2535 (2009).

Nerva, L., Varese, G. C., Falk, B. W. & Turina, M. Mycoviruses of an endophytic fungus can replicate in plant cells: evolutionary implications. Sci. Rep. 7 , 1908 (2017).

Andika, I. B. et al. Phytopathogenic fungus hosts a plant virus: a naturally occurring cross-kingdom viral infection. Proc. Natl Acad. Sci. USA 114 , 12267–12272 (2017).

Mascia, T. et al. Infection of Colletotrichum acutatum and Phytophthora infestans by taxonomically different plant viruses. Eur. J. Plant Pathol. 153 , 1001–1017 (2018).

Malloch, D. W., Pirozynski, K. A. & Raven, P. H. Ecological and evolutionary significance of mycorrhizal symbioses in vascular plants (a review). Proc. Natl Acad. Sci. USA 77 , 2113–2118 (1980).

Bonfante, P. & Genre, A. Mechanisms underlying beneficial plant–fungus interactions in mycorrhizal symbiosis. Nat. Commun. 1 , 48 (2010).

Redman, R. S., Sheehan, K. B., Stout, R. G., Rodriguez, R. J. & Henson, J. M. Thermotolerance generated by plant/fungal symbiosis. Science 298 , 1581 (2002).

Rodriguez, R. & Redman, R. More than 400 million years of evolution and some plants still can’t make it on their own: plant stress tolerance via fungal symbiosis. J. Exp. Bot. 59 , 1109–1114 (2008).

Li, C. X. et al. Unprecedented genomic diversity of RNA viruses in arthropods reveals the ancestry of negative-sense RNA viruses. eLife 4 , e05378 (2015).

PubMed Central   Google Scholar  

Shi, M. et al. Redefining the invertebrate RNA virosphere. Nature 540 , 539–543 (2016). This study identified ~1,400 RNA viruses using metatranscriptomics, which tremendously expands our current knowledge of RNA virus diversity .

Dasgupta, R., Garcia, B. H. 2nd & Goodman, R. M. Systemic spread of an RNA insect virus in plants expressing plant viral movement protein genes. Proc. Natl Acad. Sci. USA 98 , 4910–4915 (2001).

Gibbs, A. J., Wood, J., Garcia-Arenal, F., Ohshima, K. & Armstrong, J. S. Tobamoviruses have probably co-diverged with their eudicotyledonous hosts for at least 110 million years. Virus Evol. 1 , vev019 (2015).

Stobbe, A. H., Melcher, U., Palmer, M. W., Roossinck, M. J. & Shen, G. Co-divergence and host-switching in the evolution of tobamoviruses. J. Gen. Virol. 93 , 408–418 (2012).

Gibbs, A. How ancient are the tobamoviruses? Intervirology 14 , 101–108 (1980).

Varsani, A., Lefeuvre, P., Roumagnac, P. & Martin, D. Notes on recombination and reassortment in multipartite/segmented viruses. Curr. Opin. Virol. 33 , 156–166 (2018).

Briddon, R. W. et al. Alphasatellitidae: a new family with two subfamilies for the classification of geminivirus- and nanovirus-associated alphasatellites. Arch. Virol. 163 , 2587–2600 (2018).

Gnanasekaran, P. & Chakraborty, S. Biology of viral satellites and their role in pathogenesis. Curr. Opin. Virol. 33 , 96–105 (2018).

Lucia-Sanz, A. & Manrubia, S. Multipartite viruses: adaptive trick or evolutionary treat? NPJ Syst. Biol. Appl. 3 , 34 (2017).

Escriu, F., Fraile, A. & Garcia-Arenal, F. Constraints to genetic exchange support gene coadaptation in a tripartite RNA virus. PLOS Pathog. 3 , e8 (2007).

Sicard, A. et al. Gene copy number is differentially regulated in a multipartite virus. Nat. Commun. 4 , 2248 (2013).

Wu, B., Zwart, M. P., Sanchez-Navarro, J. A. & Elena, S. F. Within-host evolution of segments ratio for the tripartite genome of alfalfa mosaic virus. Sci. Rep. 7 , 5004 (2017).

Benitez-Alfonso, Y., Faulkner, C., Ritzenthaler, C. & Maule, A. J. Plasmodesmata: gateways to local and systemic virus infection. Mol. Plant Microbe Interact. 23 , 1403–1412 (2010).

Lucas, W. J. Plant viral movement proteins: agents for cell-to-cell trafficking of viral genomes. Virology 344 , 169–184 (2006).

Sicard, A., Michalakis, Y., Gutierrez, S. & Blanc, S. The strange lifestyle of multipartite viruses. PLOS Pathog. 12 , e1005819 (2016). This article reviews the ‘lifestyles’ of multipartite viruses, their peculiarities and the gaps in our understanding of their biology .

Gilmer, D., Ratti, C. & Michel, F. Long-distance movement of helical multipartite phytoviruses: keep connected or die? Curr. Opin. Virol. 33 , 120–128 (2018).

Fauquet, C. M., Mayo, M. A., Maniloff, J., Desselberger, U. & Ball, L. A. Virus Taxonomy: VIII th Report of the International Committee on Taxonomy of Viruses (Academic Press, 2005).

Liu, S. et al. Fungal DNA virus infects a mycophagous insect and utilizes it as a transmission vector. Proc. Natl Acad. Sci. USA 113 , 12803–12808 (2016).

Sacristan, S., Diaz, M., Fraile, A. & Garcia-Arenal, F. Contact transmission of tobacco mosaic virus: a quantitative analysis of parameters relevant for virus evolution. J. Virol. 85 , 4974–4981 (2011).

Jones, R. A. C. Plant and insect viruses in managed and natural environments: novel and neglected transmission pathways. Adv. Virus Res. 101 , 149–187 (2018).

Hamelin, F. M., Allen, L. J., Prendeville, H. R., Hajimorad, M. R. & Jeger, M. J. The evolution of plant virus transmission pathways. J. Theor. Biol. 396 , 75–89 (2016).

Hamelin, F. M. et al. The evolution of parasitic and mutualistic plant–virus symbioses through transmission–virulence trade-offs. Virus Res. 241 , 77–87 (2017).

Nault, L. R. Arthropod transmission of plant viruses: a new synthesis. Ann. Entomol. Soc. Am. 90 , 521–541 (1997).

Tamada, T. & Kondo, H. Biological and genetic diversity of plasmodiophorid-transmitted viruses and their vectors. J. Gen. Plant Pathol. 79 , 307–320 (2013).

CAS   Google Scholar  

Hogenhout, S. A., Ammar el, D., Whitfield, A. E. & Redinbaugh, M. G. Insect vector interactions with persistently transmitted viruses. Annu. Rev. Phytopathol. 46 , 327–359 (2008).

Dader, B. et al. Insect transmission of plant viruses: multilayered interactions optimize viral propagation. Insect Sci. 24 , 929–946 (2017).

Uzest, M. et al. A protein key to plant virus transmission at the tip of the insect vector stylet. Proc. Natl Acad. Sci. USA 104 , 17959–17964 (2007).

Ammar, E.-D., Tsai, C. W., Whitfield, A. E., Redinbaugh, M. G. & Hogenhout, S. A. Cellular and molecular aspects of rhabdovirus interactions with insect and plant hosts. Annu. Rev. Entomol. 54 , 447–468 (2009).

Brault, V., Herrbach, E. & Reinbold, C. Electron microscopy studies on luteovirid transmission by aphids. Micron 38 , 302–312 (2007).

Blanc, S. & Michalakis, Y. Manipulation of hosts and vectors by plant viruses and impact of the environment. Curr. Opin. Insect Sci. 16 , 36–43 (2016).

Safari, M., Ferrari, M. J. & Roossinck, M. J. Manipulation of aphid behavior by a persistent plant virus. J. Virol. 93 , e01781–18 (2019).

Mauck, K., Bosque-Perez, N. A., Eigenbrode, S. D., De Moraes, C. M. & Mescher, M. C. Transmission mechanisms shape pathogen effects on host–vector interactions: evidence from plant viruses. Funct. Ecol. 26 , 1162–1175 (2012).

Gallitelli, D. The ecology of Cucumber mosaic virus and sustainable agriculture. Virus Res. 71 , 9–21 (2000).

Power, A. G. & Flecker, A. S. in Infectious Disease Ecology: The Effects of Ecosystems on Disease and of Disease on Ecosystems Ch. 2 (eds Ostfeld, R. S., Keesing, F. & Eviner, V. T.) (Princeton Univ. Press, 2010).

Anderson, P. K. et al. Emerging infectious diseases of plants: pathogen pollution, climate change and agrotechnology drivers. Trends Ecol. Evol. 19 , 535–544 (2004).

Gilbertson, R. L., Batuman, O., Webster, C. G. & Adkins, S. Role of the insect supervectors Bemisia tabaci and Frankliniella occidentalis in the emergence and global spread of plant viruses. Annu. Rev. Virol. 2 , 67–93 (2015).

Fereres, A. Insect vectors as drivers of plant virus emergence. Curr. Opin. Virol. 10 , 42–46 (2015).

Simmonds, P., Aiewsakun, P. & Katzourakis, A. Prisoners of war — host adaptation and its constraints on virus evolution. Nat. Rev. Microbiol. 17 , 321–328 (2019). This study provides both a summary of viral evolutionary rates and a tentative framework to accommodate potentially conflicting long-term and short-term evolutionary rate inferences .

Stroud, J. T. & Losos, J. B. Ecological opportunity and adaptive radiation. Annu. Rev. Ecol. Evol. Syst. 47 , 507–532 (2016).

Scholthof, K. B. et al. Top 10 plant viruses in molecular plant pathology. Mol. Plant Pathol. 12 , 938–954 (2011).

Jacquemond, M. Cucumber mosaic virus. Adv. Virus Res. 84 , 439–504 (2012).

Dietzgen, R. G., Mann, K. S. & Johnson, K. N. Plant virus–insect vector interactions: current and potential future research directions. Viruses 8 , E303 (2016).

Bragard, C. et al. Status and prospects of plant virus control through interference with vector transmission. Annu. Rev. Phytopathol. 51 , 177–201 (2013).

Eastop, V. F. in Aphids As Virus Vectors (eds Harris, K. F. & Maramorosch, K.) 3–62 (Academic Press, 1977).

Li, C., Cox-Foster, D., Gray, S. M. & Gildow, F. Vector specificity of barley yellow dwarf virus (BYDV) transmission: identification of potential cellular receptors binding BYDV-MAV in the aphid, Sitobion avenae . Virology 286 , 125–133 (2001).

Bedhomme, S., Hillung, J. & Elena, S. F. Emerging viruses: why they are not jacks of all trades? Curr. Opin. Virol. 10 , 1–6 (2015).

Elena, S. F. Local adaptation of plant viruses: lessons from experimental evolution. Mol. Ecol. 26 , 1711–1719 (2017).

Remold, S. Understanding specialism when the Jack of all trades can be the master of all. Proc. Biol. Sci. 279 , 4861–4869 (2012).

Kawecki, T. J. Accumulation of deleterious mutations and the evolutionary cost of being a generalist. Am. Nat. 144 , 833–838 (1994).

Cooper, I. & Jones, R. A. Wild plants and viruses: under-investigated ecosystems. Adv. Virus Res. 67 , 1–47 (2006).

Rodriguez-Nevado, C., Montes, N. & Pagan, I. Ecological factors affecting infection risk and population genetic diversity of a novel potyvirus in its native wild ecosystem. Front. Plant Sci. 8 , 1958 (2017).

Susi, H., Filloux, D., Frilander, M. J., Roumagnac, P. & Laine, A. L. Diverse and variable virus communities in wild plant populations revealed by metagenomic tools. PeerJ 7 , e6140 (2019).

Elena, S. F., Fraile, A. & García-Arenal, F. Evolution and emergence of plant viruses. Adv. Virus Res. 88 , 161–191 (2014).

McLeish, M. J., Fraile, A. & Garcia-Arenal, F. Ecological complexity in plant virus host range evolution. Adv. Virus Res. 101 , 293–339 (2018). This article presents a comprehensive review of plant virus ecology .

Cuevas, J. M., Willemsen, A., Hillung, J., Zwart, M. P. & Elena, S. F. Temporal dynamics of intrahost molecular evolution for a plant RNA virus. Mol. Biol. Evol. 32 , 1132–1147 (2015).

Minicka, J., Rymelska, N., Elena, S. F., Czerwoniec, A. & Hasiów-Jaroszewska, B. Molecular evolution of Pepino mosaic virus during long-term passaging in different hosts and its impact on virus virulence. Ann. Appl. Biol. 166 , 389–401 (2015).

Ciota, A. T. et al. Experimental passage of St. Louis encephalitis virus in vivo in mosquitoes and chickens reveals evolutionarily significant virus characteristics. PLOS ONE 4 , e7876 (2009).

Greene, I. P. et al. Effect of alternating passage on adaptation of sindbis virus to vertebrate and invertebrate cells. J. Virol. 79 , 14253–14260 (2005).

Turner, P. E. & Elena, S. F. Cost of host radiation in an RNA virus. Genetics 156 , 1465–1470 (2000).

Bedhomme, S., Lafforgue, G. & Elena, S. F. Multihost experimental evolution of a plant RNA virus reveals local adaptation and host-specific mutations. Mol. Biol. Evol. 29 , 1481–1492 (2012). This study provides experimental evidence for the possible existence of no-cost generalists in plant viruses .

Hillung, J., Cuevas, J. M., Valverde, S. & Elena, S. F. Experimental evolution of an emerging plant virus in host genotypes that differ in their susceptibility to infection. Evolution 68 , 2467–2480 (2014).

Lalic, J., Agudelo-Romero, P., Carrasco, P. & Elena, S. F. Adaptation of tobacco etch potyvirus to a susceptible ecotype of Arabidopsis thaliana capacitates it for systemic infection of resistant ecotypes. Phil. Trans. R. Soc. B 365 , 1997–2007 (2010).

Charron, C. et al. Natural variation and functional analyses provide evidence for co-evolution between plant eIF4E and potyviral VPg. Plant J. 54 , 56–68 (2008).

Jenner, C. E., Wang, X., Ponz, F. & Walsh, J. A. A fitness cost for Turnip mosaic virus to overcome host resistance. Virus Res. 86 , 1–6 (2002).

Hillung, J., Garcia-Garcia, F., Dopazo, J., Cuevas, J. M. & Elena, S. F. The transcriptomics of an experimentally evolved plant–virus interaction. Sci. Rep. 6 , 24901 (2016).

McCallum, E. J., Anjanappa, R. B. & Gruissem, W. Tackling agriculturally relevant diseases in the staple crop cassava ( Manihot esculenta ). Curr. Opin. Plant Biol. 38 , 50–58 (2017).

Almeida, R. P. et al. Ecology and management of grapevine leafroll disease. Front. Microbiol. 4 , 94 (2013).

Walls, J., Rajotte, E. & Rosa, C. The past, present, and future of barley yellow dwarf management. Agriculture 9 , 23 (2019).

Pinel-Galzi, A., Traore, O., Sere, Y., Hebrard, E. & Fargette, D. The biogeography of viral emergence: rice yellow mottle virus as a case study. Curr. Opin. Virol. 10 , 7–13 (2015).

Fargette, D. et al. Molecular ecology and emergence of tropical plant viruses. Annu. Rev. Phytopathol. 44 , 235–260 (2006).

Jones, R. A. Plant virus emergence and evolution: origins, new encounter scenarios, factors driving emergence, effects of changing world conditions, and prospects for control. Virus Res. 141 , 113–130 (2009). This article reviews various anthropogenic factors associated with the emergence of plant viruses and the ongoing challenges in mitigating emerging disease threats .

Pagan, I. et al. Effect of biodiversity changes in disease risk: exploring disease emergence in a plant–virus system. PLOS Pathog. 8 , e1002796 (2012).

Roossinck, M. J. & Garcia-Arenal, F. Ecosystem simplification, biodiversity loss and plant virus emergence. Curr. Opin. Virol. 10 , 56–62 (2015).

Rodelo-Urrego, M. et al. Landscape heterogeneity shapes host–parasite interactions and results in apparent plant–virus codivergence. Mol. Ecol. 22 , 2325–2340 (2013).

Rocha, C. S. et al. Brazilian begomovirus populations are highly recombinant, rapidly evolving, and segregated based on geographical location. J. Virol. 87 , 5784–5799 (2013).

Keesing, F. et al. Impacts of biodiversity on the emergence and transmission of infectious diseases. Nature 468 , 647–652 (2010). This article addresses the impacts of reduced biodiversity on disease transmission .

Lima, A. T. et al. Synonymous site variation due to recombination explains higher genetic variability in begomovirus populations infecting non-cultivated hosts. J. Gen. Virol. 94 , 418–431 (2013).

Thingstad, T. F. & Lignell, R. Theoretical models for the control of bacterial growth rate, abundance, diversity and carbon demand. Aquat. Microb. Ecol. 13 , 19–27 (1997).

Coutinho, F. H. et al. Marine viruses discovered via metagenomics shed light on viral strategies throughout the oceans. Nat. Commun. 8 , 15955 (2017).

Coutinho, F. H., Gregoracci, G. B., Walter, J. M., Thompson, C. C. & Thompson, F. L. Metagenomics sheds light on the ecology of marine microbes and their viruses. Trends Microbiol. 26 , 955–965 (2018).

Mitchell, C. E. & Power, A. G. Release of invasive plants from fungal and viral pathogens. Nature 421 , 625–627 (2003).

Borer, E. T., Hosseini, P. R., Seabloom, E. W. & Dobson, A. P. Pathogen-induced reversal of native dominance in a grassland community. Proc. Natl Acad. Sci. USA 104 , 5473–5478 (2007).

Malmstrom, C. M., McCullough, A. J., Johnson, H. A., Newton, L. A. & Borer, E. T. Invasive annual grasses indirectly increase virus incidence in California native perennial bunchgrasses. Oecologia 145 , 153–164 (2005). This article addresses the impacts of an invasive plant species on viral dynamics in native plants .

Faillace, C. A., Lorusso, N. S. & Duffy, S. Overlooking the smallest matter: viruses impact biological invasions. Ecol. Lett. 20 , 524–538 (2017). This article reviews the impacts of rapidly evolving plant viruses on plant community structure within a biological invasion framework .

Cervera, H., Ambros, S., Bernet, G. P., Rodrigo, G. & Elena, S. F. Viral fitness correlates with the magnitude and direction of the perturbation induced in the host’s transcriptome: the Tobacco Etch Potyvirus-Tobacco Case Study. Mol. Biol. Evol. 35 , 1599–1615 (2018).

Alizon, S., Hurford, A., Mideo, N. & Van Baalen, M. Virulence evolution and the trade-off hypothesis: history, current state of affairs and the future. J. Evol. Biol. 22 , 245–259 (2009).

Anderson, R. M. & May, R. M. Coevolution of hosts and parasites. Parasitology 85 , 411–426 (1982).

Doumayrou, J., Avellan, A., Froissart, R. & Michalakis, Y. An experimental test of the transmission–virulence trade-off hypothesis in a plant virus. Evolution 67 , 477–486 (2013).

Froissart, R., Doumayrou, J., Vuillaume, F., Alizon, S. & Michalakis, Y. The virulence–transmission trade-off in vector-borne plant viruses: a review of (non-)existing studies. Phil. Trans. R. Soc. B 365 , 1907–1918 (2010). This article reviews our current understanding of the transmission–virulence trade-off hypothesis in the context of plant viruses .

Leggett, H. C., Buckling, A., Long, G. H. & Boots, M. Generalism and the evolution of parasite virulence. Trends Ecol. Evol. 28 , 592–596 (2013).

Roossinck, M. J. A new look at plant viruses and their potential beneficial roles in crops. Mol. Plant Pathol. 16 , 331–333 (2015).

Roossinck, M. J. Plants, viruses and the environment: ecology and mutualism. Virology 479–480 , 271–277 (2015). This review addresses the paradigm shift away from viewing viruses as antagonistic pathogens towards viewing them as possible mutualists .

Shates, T. M., Sun, P., Malmstrom, C. M., Dominguez, C. & Mauck, K. E. Addressing research needs in the field of plant virus ecology by defining knowledge gaps and developing wild dicot study systems. Front. Microbiol. 9 , 3305 (2018).

Fraile, A. & Garcia-Arenal, F. The coevolution of plants and viruses: resistance and pathogenicity. Adv. Virus Res. 76 , 1–32 (2010).

Calil, I. P. & Fontes, E. P. B. Plant immunity against viruses: antiviral immune receptors in focus. Ann. Bot. 119 , 711–723 (2017).

Malmstrom, C. M. & Alexander, H. M. Effects of crop viruses on wild plants. Curr. Opin. Virol. 19 , 30–36 (2016).

Prendeville, H. R., Ye, X., Morris, T. J. & Pilson, D. Virus infections in wild plant populations are both frequent and often unapparent. Am. J. Bot. 99 , 1033–1042 (2012).

Remold, S. K. Unapparent virus infection and host fitness in three weedy grass species. J. Ecol. 90 , 967–977 (2002).

Fraile, A. et al. Environmental heterogeneity and the evolution of plant-virus interactions: viruses in wild pepper populations. Virus Res. 241 , 68–76 (2017).

Faure, D., Simon, J. C. & Heulin, T. Holobiont: a conceptual framework to explore the eco-evolutionary and functional implications of host–microbiota interactions in all ecosystems. New Phytol. 218 , 1321–1324 (2018).

Grasis, J. A. The intra-dependence of viruses and the holobiont. Front. Immunol. 8 , 1501 (2017).

Harth, J. E., Ferrari, M. J., Tooker, J. F. & Stephenson, A. G. Zucchini yellow mosaic virus infection limits establishment and severity of powdery mildew in wild populations of Cucurbita pepo. Front. Plant Sci. 9 , 792 (2018).

Gibbs, A. A plant virus that partially protects its wild legume host against herbivores. Intervirology 13 , 42–47 (1980).

Davis, T. S., Bosque-Perez, N. A., Foote, N. E., Magney, T. & Eigenbrode, S. D. Environmentally dependent host–pathogen and vector–pathogen interactions in the Barley yellow dwarf virus pathosystem. J. Appl. Ecol. 52 , 1392–1401 (2015).

Hily, J. M., Poulicard, N., Mora, M. A., Pagan, I. & Garcia-Arenal, F. Environment and host genotype determine the outcome of a plant–virus interaction: from antagonism to mutualism. New Phytol. 209 , 812–822 (2016). This study provides compelling evidence that conditional interactions of plant viruses, plant genotypes and the environment modulate the outcome of symbiosis .

Westwood, J. H. et al. A viral RNA silencing suppressor interferes with abscisic acid-mediated signalling and induces drought tolerance in Arabidopsis thaliana . Mol. Plant Pathol. 14 , 158–170 (2013).

Xu, P. et al. Virus infection improves drought tolerance. New Phytol. 180 , 911–921 (2008).

Prasch, C. M. & Sonnewald, U. Simultaneous application of heat, drought, and virus to Arabidopsis plants reveals significant shifts in signaling networks. Plant Physiol. 162 , 1849–1866 (2013).

Berges, S. E. et al. Interactions between drought and plant genotype change epidemiological traits of cauliflower mosaic virus. Front. Plant Sci. 9 , 703 (2018).

Bera, S., Fraile, A. & Garcia-Arenal, F. Analysis of fitness trade-offs in the host range expansion of an RNA virus, tobacco mild green mosaic virus. J. Virol. 92 , e01268–18 (2018).

Zhang, Y. Z., Shi, M. & Holmes, E. C. Using metagenomics to characterize an expanding virosphere. Cell 172 , 1168–1172 (2018).

Saunders, K., Bedford, I. D., Yahara, T. & Stanley, J. Aetiology: the earliest recorded plant virus disease. Nature 422 , 831 (2003).

Lesnaw, J. A. & Ghabrial, S. A. Tulip breaking: past, present, and future. Plant Dis. 84 , 1052–1060 (2000).

Ivanowski, D. Ueber die Mosaikkrankheit der Tabakspflanze. Bull. Acad. Imp. Sci. 35 , 67–70 (1892).

Beijerinck, W. M. Ueber ein contagium vivum fluidum als Ursache der Fleckenkrankheit der Tabaksblatter. Verh. Kon. Akad. Wetensch. 5 , 3–21 (1898).

Stanley, W. M. Isolation of a crystalline protein possessing the properties of tobacco-mosaic virus. Science 81 , 644–645 (1935).

Kausche, G. A., Pfankuch, E. & Ruska, H. Die Sichtbarmachung von pflanzlichem Virus im Übermikroskop. Naturwissenschaften 27 , 292–299 (1939).

Bernal, J. D. & Fankuchen, I. Structure types of protein crystals from virus-infected plants. Nature 139 , 923–924 (1937).

Fraenkel-Conrat, H. The genetic code of a virus. Sci. Am. 211 , 47–54 (1964).

Anandalakshmi, R. et al. A viral suppressor of gene silencing in plants. Proc. Natl Acad. Sci. USA 95 , 13079–13084 (1998).

Hamilton, A. J. & Baulcombe, D. C. A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 286 , 950–952 (1999).

Guo, Z. et al. Identification of a new host factor required for antiviral RNAi and amplification of viral siRNAs. Plant Physiol. 176 , 1587–1597 (2018).

Baltimore, D. Expression of animal virus genomes. Bacteriol. Rev. 35 , 235–241 (1971).

Bolduc, B. et al. vConTACT: an iVirus tool to classify double-stranded DNA viruses that infect Archaea and Bacteria . PeerJ 5 , e3243 (2017).

Mihara, T. et al. Linking virus genomes with host taxonomy. Viruses 8 , 66 (2016).

Evans, G. A. Host Plant List of The Whiteflies (Aleyrodidae) of The World (USDA Animal Plant Health Inspection Service, 2007).

De Barro, P. J., Liu, S. S., Boykin, L. M. & Dinsdale, A. B. Bemisia tabaci : a statement of species status. Annu. Rev. Entomol. 56 , 1–19 (2011).

Huang, Y., Niu, B., Gao, Y., Fu, L. & Li, W. CD-HIT Suite: a web server for clustering and comparing biological sequences. Bioinformatics 26 , 680–682 (2010).

Katoh, K. & Standley, D. M. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol. Biol. Evol. 30 , 772–780 (2013).

Guindon, S. et al. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst. Biol. 59 , 307–321 (2010).

Clark, K., Karsch-Mizrachi, I., Lipman, D. J., Ostell, J. & Sayers, E. W. GenBank. Nucleic Acids Res. 44 , D67–D72 (2016).

Ratnasingham, S. & Hebert, P. D. bold: the Barcode of Life Data System ( http://www.barcodinglife.org ). Mol. Ecol. Notes 7 , 355–364 (2007).

Gerlt, J. A. et al. Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST): a web tool for generating protein sequence similarity networks. Biochim. Biophys. Acta 1854 , 1019–1037 (2015).

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Acknowledgements

The authors are grateful to Y. Michalakis (Centre national de la recherche scientifique, France) and A. Gibbs (Australian Nation University, Australia) for helpful comments and suggestions. P.L. was supported by the European Union: European Regional Development Fund (ERDF), by the Conseil Régional de La Réunion and by the Centre de Coopération internationale en Recherche agronomique pour le Développement (CIRAD). S.F.E. was supported by a grant (BFU2015-65037-P) from Spain Ministry of Science, Innovation and Universities–ERDF.

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Computational Biology Division, Department of Integrative Biomedical Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa

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Instituto de Biología Integrativa de Sistemas (I2SysBio), CSIC-UV, Paterna, València, Spain

Santiago F. Elena

The Santa Fe Institute, Santa Fe, NM, USA

Research Office, University of Cape Town, Cape Town, South Africa

Dionne N. Shepherd

CIRAD, UMR BGPI, Montpellier, France

Philippe Roumagnac

BGPI, CIRAD, INRA, Montpellier SupAgro, University of Montpellier, Montpellier, France

The Biodesign Center for Fundamental and Applied Microbiomics, Center for Evolution and Medicine, School of Life Sciences, Arizona State University, Tempe, AZ, USA

Arvind Varsani

Structural Biology Research Unit, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa

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P.L., D.P.M., S.F.E., D.N.S., P.R. and A.V. wrote and edited the manuscript. P.L. and A.V. undertook the analyses for the data presented in figures 1–3.

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Plant viruses dataset: https://lefeup.github.io/plantviruses/

These invertebrate animals have exoskeletons, segmented bodies and paired jointed appendages. Arthropods belong to the phylum Euarthropoda that includes insects, arachnids, myriapods and crustaceans.

These enzymes catalyse the synthesis of RNA from an RNA template. RNA-dependent RNA polymerases are essential to the replication of viruses that have no DNA stage.

Some plant viruses encode these proteins to facilitate cell-to-cell movement of viral particles and/or uncoated viral nucleic acids. They frequently function by increasing the size exclusion limits of plasmodesmata.

Brassica is a genus in the mustard family (Brassicaceae) of plants, which includes cabbage, lettuce and cauliflower.

Angiosperms are also known as flowering plants and are the most diverse group of land plants. While both gymnosperms and angiosperms produce seeds, angiosperms are characterized by the presence of flowers, an endosperm within the seeds and the inclusion of seeds within fruits.

These microscopic channels traverse plant cell walls enabling intercellular trafficking of macromolecules.

This class of plant parasites comprises organisms in the orders Plasmodiophorida and Phagomyxida. They have long been recognized as a basal group to fungi, but recent molecular phylogenetic analysis suggests that they are more closely related to protozoa in the phylum Cercozoa.

This order of insects includes insects such as aphids, cicadas, leafhoppers and planthoppers. Most hemipterans feed on plant sap with their sucking and piercing mouthparts.

This is the body cavity in arthropods wherein haemolymph (plasma with haemocytes) circulates.

These small sap-sucking insects are members of the superfamily Aphidoidea in the Hemiptera order.

The phloem is the vascular system in plants within which soluble organic compounds that are produced during photosynthesis are transported.

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Lefeuvre, P., Martin, D.P., Elena, S.F. et al. Evolution and ecology of plant viruses. Nat Rev Microbiol 17 , 632–644 (2019). https://doi.org/10.1038/s41579-019-0232-3

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Published : 16 July 2019

Issue Date : October 2019

DOI : https://doi.org/10.1038/s41579-019-0232-3

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Oncolytic virus therapy in cancer: A current review

Jonathan santos apolonio.

Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil

Vinícius Lima de Souza Gonçalves

Universidade Estadual do Sudoeste da Bahia, Campus Vitória da Conquista, Vitória da Conquista 45083-900, Bahia, Brazil

Maria Luísa Cordeiro Santos

Marcel silva luz, joão victor silva souza, samuel luca rocha pinheiro, wedja rafaela de souza, matheus sande loureiro, fabrício freire de melo.

Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil. rb.moc.oohay@olemerierf

Corresponding author: Fabrício Freire de Melo, PhD, Professor, Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Rua Hormindo Barros, 58, Quadra 17, Lote 58, Vitória da Conquista 45029-094, Bahia, Brazil. rb.moc.oohay@olemerierf

In view of the advancement in the understanding about the most diverse types of cancer and consequently a relentless search for a cure and increased survival rates of cancer patients, finding a therapy that is able to combat the mechanism of aggression of this disease is extremely important. Thus, oncolytic viruses (OVs) have demonstrated great benefits in the treatment of cancer because it mediates antitumor effects in several ways. Viruses can be used to infect cancer cells, especially over normal cells, to present tumor-associated antigens, to activate “danger signals” that generate a less immune-tolerant tumor microenvironment, and to serve transduction vehicles for expression of inflammatory and immunomodulatory cytokines. The success of therapies using OVs was initially demonstrated by the use of the genetically modified herpes virus, talimogene laherparepvec, for the treatment of melanoma. At this time, several OVs are being studied as a potential treatment for cancer in clinical trials. However, it is necessary to be aware of the safety and possible adverse effects of this therapy; after all, an effective treatment for cancer should promote regression, attack the tumor, and in the meantime induce minimal systemic repercussions. In this manuscript, we will present a current review of the mechanism of action of OVs, main clinical uses, updates, and future perspectives on this treatment.

Core Tip: Oncolytic viruses are organisms able to infect and lyse the tumor cells beyond stimulating the immune system to combat the disease. The clinical use of oncolytic viruses has shown to have positive results in the treatment of some types of cancers, contributing to reducing the tumor. Furthermore, the combined use of these viruses and other antitumor therapies have contributed to better prognosis in the patient’s clinical condition.

INTRODUCTION

The first theories about the possible use of viruses to combat tumor cells date from the early 20 th century with the description in 1904 of a woman with acute leukemia who presented remission of the clinical picture and a patient with cervical cancer in 1912 that demonstrated extensive tumor necrosis, both after a viral infection[ 1 ]. Thereafter, between 1950 and 1980, influenced by the possibility of developing a therapy for cancer, many studies were performed with different types of wild viruses aiming at an oncolytic action; however, the goal was not achieved due to the non-existence of necessary tools to control the viral pathogenesis and direct the virus to specific targets[ 2 ]. Viruses can be used to infect cancer cells, specifically over normal cells, to present tumor-associated antigens, to activate “danger signals” that generate a less immune-tolerant tumor microenvironment, and to serve transduction vehicles for expression of inflammatory and immunomodulatory cytokines[ 3 ]. Currently, in order to overcome these obstacles, the updates in the field of genetics seek to increase the specificity and efficacy of some viruses in infecting the abnormal cells through mechanisms such as gene deletion and the combined use of viruses and immune checkpoint inhibitors (ICIs)[ 4 ].

The oncolytic viruses (OVs) are organisms able to identify, infect, and lyse different cells in the tumor environment, aiming to stabilize and decrease the tumor progression. They can present a natural tropism to the cancer cells or be oriented genetically to identify specific targets[ 5 ]. Several OVs are being studied as a potential treatment for cancer in clinical trials[ 6 ]. Moreover, the OVs are capable of contributing to the stimulation of the immune system against the tumor cells, influencing the development of an antitumor response[ 7 ].

It is known that there are several evasion mechanisms in the tumor environment that contribute to the downregulation of the immune system, positively influencing the stability and progression of the disease even in immunocompetent patients[ 8 ]. Antigen presenting cells can be prevented from presenting tumor antigens to the T cells correctly, which contributes to the non-activation or discouragement of these cells[ 9 ]. Moreover, certain types of tumors can promote an abnormal stimulation of immune checkpoint receptors in T cells, like the cytotoxic T lymphocyte-associated antigen 4 and the programmed cell death protein 1/programmed death ligand 1(PD-L1), both related to the negative regulation of the inflammatory response and immune system homeostasis contributing to apoptosis and inhibition of proliferation of T cells[ 10 ]. In addition, the excess of tumor-associated macrophages, main lymphocytes regarding the inflammatory response against the tumor, are also an important mechanism of immune evasion since they have some similar functions and features to type M2 macrophages, which are responsible for tissue repair and immune response regulation. Thus, the abnormal rise of tumor-associated macrophages has been related to the downregulation of inflammation and increase of tumor growth rates[ 11 ].

Therefore, the clinical use of OVs emerges as an alternative to modifying the tumor environment from a state of immune desert caused by the evasion mechanisms that contribute to tumor progression, to an inflamed state, where the immune system is able to kill the abnormal cells[ 12 ]. In addition, the viruses present different mechanisms that would lead the infected cells to a cell lysis process, contributing to tumor cell death and increasing the efficacy of the immunotherapy[ 4 ]. This review will encompass the viral mechanisms responsible for the oncolytic action of OVs, the clinical use of these viruses in certain tumors, and the future perspectives about their use.

General mechanism

OVs are able to infect abnormal cells through specific targets, such as nuclear transcription factors and among them human telomerase reverse transcriptase, prostate specific antigen, cyclooxygenase-2, osteocalcin, and surface markers as prostate-specific membrane antigen, folate receptor, CD20, endothelial growth factor receptor, and Her2/neu, which are substances produced by the tumor cells[ 5 ]. Furthermore, the deletion of pathogenic viral genes in the laboratory in order to increase the selectivity to the tumor cells and decrease the aggressiveness of the OVs to normal tissues is also possible[ 13 ].

The administration route of OVs is intrinsically related to the type of tumor to be treated, given that the virus pathway directly influences the effectiveness of the therapy due to the virus availability on-site and the natural barrier of the organism of combat to antigens. The distribution can occur via intraperitoneal, intrathecal, subcutaneous, intratumoral, which provides greater control of viral quantity in the tumor environment and less adverse effects, and intravenous, which is related to the treatment of distant metastases[ 14 ].

Regarding the mechanisms of immune evasion by the tumor, the cancer cells can present certain alterations in the expression and activation of some mechanisms, such as protein kinase R and interferon 1 signaling pathway, which interferes in the response to viral infections, programmed apoptosis, and maturation of inflammatory cells. The modifications in the antiviral response, allied to viral factors capable of preventing apoptosis, allow OVs to survive longer in cancer cells and consequently to conclude the life cycle and maturation to the lytic phase[ 15 ].

The presence of viruses in the human organism stimulates the recognition of different immune signs related to the virus structure, such as viral proteins, RNA, DNA, and viral capsid, the pathogen-associated molecular patterns (PAMPs)[ 16 ]. Dendritic cells, upon recognition of the PAMPs through toll-like receptors (TLRs), which are pattern recognition receptors, stimulate production of inflammatory molecules with antiviral characteristics, like the type 1 interferons, tumor necrosis factor alpha (TNF-alpha) and cytokines such as interleukin 2 (IL-2), important mechanisms of recruitment of immune cells, and maintenance of the inflammatory environment[ 17 ].

TNF-alpha is related to response to the viral infection, positively regulating the expression of class 1 major histocompatibility complex in the cell membrane and positively influencing the action of caspase enzyme and cell apoptosis on some tumors[ 18 ]. This interferon is capable of stimulating cancer cell death through mechanisms that contribute to necrosis and apoptosis, generating thrombotic events through its antiangiogenic effects, which can lead to the destruction of some blood vessels responsible for the blood supply of the tumor[ 19 ]. TNF-alpha is also related to the stimulation of T helper cells type 1 (Th1) response, increase of the cytotoxicity of natural killer cells, and maturation of antigens presenting cells[ 18 ].

Studies have shown that IL-2 is related to the stimulation of cytotoxic lymphocytes and activation of T cell response, contributing to maturation and expansion of CD8+ T cells (TCD8) and natural killer cells, along with positive regulation of CD4+ T cells (TCD4). IL-2 is also capable of regulating T regulatory cell action and homeostasis, creating an inflammatory environment favorable for combating the tumor[ 20 ]. Furthermore, the Th1 inflammatory profile was also related to the decrease of T regulatory cells, increased rates of TCD4 and TCD8 effector cells, stimulation and differentiation of T lymphocytes as well as the maturation of dendritic cells, which contributes to the reversal of the immunosuppressive state of the tumor and promotes an inflammatory response[ 21 ].

In addition to the damage caused by the inflammatory response, the viral action inside the cell is also an important factor in the lysis and death of the aberrant cells. The presence of OVs could stimulate some dysfunction of organelles, such as the endoplasmic reticulum, mitochondria, or lysosome, compromising the normal cellular function. Moreover, the virus can stimulate oxidative stress through the production of reactive nitrogen species and endoplasmic reticulum stress, which is related to an increase of intracellular calcium levels[ 17 ], contributing to the stabilization and decrease of the tumor.

The combined use of cell checkpoint blockers and OVs is an important mechanism to increase viral survival rates in the human organism, given that it contributes to the stimulation of an inflammatory response against the tumor. Through negative regulation of PD-L1, the tumor can circumvent the immune system, avoiding the maturation of T cells. In this way, PD-L1 inhibition was capable of stimulating a response with a Th1 profile, contributing to the appearance of TCD8 cells against the tumors and stimulating natural killer cell action[ 22 ]. Furthermore, studies have demonstrated that the administration of the OVs and monoclonal antibodies that inhibit the action of cytotoxic T lymphocyte-associated antigen 4 contributed to enhancing the effectiveness of immunotherapy[ 21 ].

The aforementioned mechanisms contribute to different types of elimination of the tumor cells, such as autophagic cell death, apoptosis, pyroptosis, and necrosis, leading to the production of immune signs related to the cell damage: damage-associated molecular patterns (DAMPs), like high mobility group box 1 protein and ATP. The DAMPs are important elements in the stimulation of the dendritic cell maturation process and contribute to the presentation of tumor-associated antigens to the immune cells through the cross-presentation between DAMPs and tumor-associated antigens, which leads to the perpetuation of the inflammatory response process[ 23 ]. Therefore, cellular lysis allows the liberation of the viruses in the extracellular environment and subsequent infection of other tumor cells, creating a chain reaction of combat to the tumor[ 16 ]. Besides that, the cell death contributes to the release of tumor antigens liable to be identified by immune cells in the inflammatory environment, stimulating a response against tumor cells, even in the uninfected ones, by the OVs[ 15 ].

The main mechanisms of action of OVs are represented in (Figure ​ (Figure1 1 ).

Mechanism of action of oncolytic viruses. Initially, oncolytic viruses can be administered by different pathways, such as intratumoral, subcutaneous, intraperitoneal, and intrathecal. Natural tropism and genetic targeting are responsible for favoring the arrival of oncolytic viruses to the tumor cells. Thereafter, the oncolytic viruses start to recognize the abnormal cells through substances expressed in the tumor environment and can use different receptors to connect and infect the host cell. From this point, the virus starts to use the cellular machinery for its replication process, producing viral proteins, reducing the cell function, stimulating oxidative stress states and contributing to the activation of some pathways related to the autophagic processes. At the same time, the antigen-presenting cells encompass some viral organisms, generating the formation of an endosomal vesicle that will merge with a lysosomal vesicle and will cause the digestion of the virus, providing smaller viral particles to be processed inside the cell. Later, the expression of the major histocompatibility complex class 2 together with the viral proteins on the cell surface occurs, creating a favorable environment for the antigenic presentation and subsequent activation and stimulation of the CD4+ T cells and CD8+ T cells, the first related to the production of cytokines responsible for contributing to the migration and maturation processes of inflammatory cells, and the second related to the direct action against the infected cells. Finally, the viral action and the immune response contribute to the destruction of the tumor cells releasing the viral progeny in the host organism allowing it to infect other abnormal cells and restart the process of combatting the tumor. Furthermore, cell death also releases tumor antigens that the immune system can identify, contributing to the formation of new inflammatory responses capable of acting both in the tumor environment and even in metastatic sites.

Adenovirus: The adenoviruses are non-enveloped organisms with double-stranded linear DNA and an icosahedral capsid with three main proteins, hexon, penton base, and fiber, which when identified by the immune system contribute to the emergence of an antiviral response. There are more than 80 human types of adenoviruses that belong to the Adenoviridae family[ 24 ]. These viruses have a high tropism for different tissues of the organism, including ocular, respiratory, enteric, renal, and lymphoid and are able to use several receptors, such as human coxsackie-adenovirus receptor, CD86, CD46, and CD80 to enter the host cells[ 25 ]. Moreover, due to its capacity of serving as a viral vector[ 24 ], allied to their chemical and thermal stability outside the cell, various mechanisms of cellular entry, and the great knowledge about their biology, the adenoviruses have been used for the development of different immune therapies[ 26 ].

The viral replication process starts inside the cellular nucleus, inducing the expression and liberation of some proteins in the cytoplasm such as E1a and E1b, which are related to the stimulation of the autophagy process. This mechanism induces the production of some autophagosomes that can later merge with lysosomes resulting in the death of organelles or even the full cell[ 27 ]. Furthermore, research has shown that in tumor cells the expression of E1a can be related to the stimulation of the production of autophagic complexes, and E1b possibly supports the potentiation of action of these complexes, both contributing to the stabilization and decrease of the tumor[ 28 ].

When identifying and responding to different proteins of the viral capsid of adenoviruses, the human organism starts producing several inflammatory cytokines, such as IL-12 and TNF-alpha[ 29 ], which are related to the stimulation of cytotoxic cells like natural killer cells and TCD8, besides contribution in the maturation of immune cells and against the tumor. The type 5 Ad is commonly used for oncolytic therapy, since it can be detected by TLRs in the cellular membrane (TLR-2) or inside the cell (TLR-9) teasing the stimulation of different mechanisms in order to create a Th1 profile inflammatory response[ 29 ]. Moreover, the Adenoviruses can activate other pathways of the immune system, such as the complement system stimulating the opsonization processes, increasing the migration rates of inflammatory cells and production of inflammatory cytokines[ 23 ], which contributes to destroying infected cells.

Finally, the cellular stress caused by the viral infection and the inflammatory process lead to tumor cell death through necrosis, autophagy, or apoptosis and further liberation of DAMPs or PAMPs in the inflammatory environment, stimulating the maturation and migration of inflammatory cells as well as the production of cytokines. Furthermore, in addition to the direct tumor cell killing, the adenoviruses are capable of initiating the formation of an antitumor immune memory that contributes to the combat in metastatic sites[ 25 ]. Table ​ Table1 1 shows some genetic modifications to improve the adenoviruses oncolytic action.

Genetic modifications in the adenovirus

Ads: Adenoviruses; CD40L: CD40 ligand; DSG-2: Desmoglein 2; FP3: Farnesylated protein 3; HVR5: Hypervariable region 5; ICOSL: Inducible co-stimulator ligand; IL-24: Interleukin 24; MDA-7: Melanoma differentiation-associated gene-7; pRB: Retinoblastoma protein; tCCN1: Truncated cellular communication network factor 1; TGFBRII: Transforming growth factor-beta receptor II; TIMP2: Tissue inhibitor of metalloproteinases 2.

Protoparvovirus : The Protoparvoviruses are single-stranded DNA, non-enveloped viruses that belong to the Parvoviridae family. They are capable of infecting mammalian cells, including human beings, through fixation factors such as the transferrin receptor or glycosidic substances like the N-acetylneuraminic acid that is expressed on the cellular membrane and contributes to an environment favorable to viral fixation in the cell[ 30 ].

The major capsid protein VP1 is a protein that coordinates the penetration of protoparvoviruses in the host cell by an endocytosis process and enables the destruction of the endocytic vesicle inside the cell and further liberation of viral proteins in the cytoplasm. Moreover, VP1 has nuclear localization signals responsible for assisting the viral protein displacement to the cell nucleus[ 31 ]. From this point, the virus can remain inert until the beginning of the cellular division process when during the S/G2 phases through protein NS1 action, it can block the cell genome replication and allow the integration of viral material with the host genetic material to ensure the viral survival[ 31 ].

H-1PV can produce an oxidative stress state through the increase in levels of reactive oxygen and nitrogen species through NS1 protein action inside the cell. NS1 is also related to the regulation of RNA viral replication, leading to the destruction of genetic material and activation of apoptosis pathways with later cell death. Furthermore, the virus can stimulate the liberation of proteases from the lysosome to the cytoplasm causing cellular necrosis of tumor cells[ 17 ].

In addition, the protoparvoviruses are capable of triggering an inflammatory response with antitumor characteristics generating the production of cytokines with a Th1 profile like IL-2 and TNF-alpha, which[ 32 ] sets an inflammatory environment able to deal with the tumor cells. H-1PV also contributes to the stimulation of T lymphocytes like TCD8, cytotoxic cells, and the auxiliary cells TCD4 and formation of an immune memory against the tumor[ 33 ].

During the lytic phase, the viral action enables the increase of membrane permeability of lysosomes that allows the passage of the cathepsins enzymes to the cytoplasm and decreases the action of inhibitory agents of these proteases. Both factors play an important role in the gathering of cathepsins in the cellular cytoplasm, stimulation of their action, and contribution to the apoptosis pathways and to tumor cell death[ 34 ]. Moreover, the expression of NS1 contributes to cellular apoptosis through damage to the genetic material, activation and stimulation of caspase action, and the generation of oxidative stress processes, bypassing the apoptotic evasion mechanism of the tumor cells[ 35 ].

Vaccinia virus : The vaccinia viruses (VACVs) are enveloped viruses with double-stranded linear DNA and belong to the Poxviridae family. They were used for smallpox vaccination in 1796, and currently after the eradication of this disease, their scientific use is aimed at the creation of vaccines and therapies for other pathologies[ 36 ]. One of the members of this family is the Pexa-Vec (pexastimogene devacirepvec, JX-594), which is genetically modified to possess the granulocyte-macrophage colony-stimulating factor (GM-CSF) along with thymidine kinase ( TK ) gene deletion in order to increase the tropism to the tumor cells and limit the replication to the cells that express aberrant levels of TK[ 37 ].

The administration of VACVs in the tumor environment was related to the stimulation and expression of GM-CSF and IL-24, factors that together could contribute to stabilize and provide tumor cell death. GM-CSF is related to the maturation and differentiation of immune system cells like dendritic cells and neutrophils, which create an inflammatory environment that enables the combat of the tumor, and IL-24 inhibits tumor angiogenesis, positively influencing the apoptosis pathways and the formation of an antitumor response while inhibiting the formation of tumor metastases[ 38 ].

The viral action of some VACVs strains stimulate different cell death pathways such as necrosis and apoptosis, leading to the liberation of substances related to damage and danger, like ATP and high mobility group box 1 protein, that provides an immunogenic environment. Thereafter, the DAMPs support the cross-presentation between them and the tumor antigens, stimulating the TCD8 cell action and contributing to the stimulation of the antitumor response[ 39 ]. Furthermore, the Pexa-Vec has a tropism for endothelial cells that are responsible for tumor growth through the expression of vascular endothelial growth factor or fibroblast growth factor. It leads to the destruction of vasculature that irrigates the tumor and consequently a tissue necrosis process and decreasing of the tumor extension[ 40 ]. Some genetic modifications in the VACVs and updates in oncolytic therapy are listed in Table ​ Table2 2 .

Genetic modifications in the vaccinia virus

Ab: Agonist antibody; GM-CSF: Granulocyte-macrophage colony-stimulating factor; IL-12: Interleukin 12; NK: Natural killer; TK: Thymidine kinase; VV: Vaccinia virus.

Reovirus : Respiratory enteric orphan virus (Reovirus) is a non-enveloped and double-stranded RNA virus that belongs to the Reoviridae family, which has a wide range of hosts (fungi, plants, fish, mammals, among others)[ 41 , 42 ]. This name is due to the isolation of the pathogen in the respiratory and gastrointestinal tract and the inability to cause any known human diseases[ 43 , 44 ]. Interestingly, this last characteristic is strongly correlated to the successful use of reoviruses in oncolytic therapy as well. The primary connection of reoviruses to an oncolytic role was found in 1977 when a study demonstrated that they have a tropism for “transformed cells” and that normal cells are resistant to the virus[ 45 ]. This information led, consequently, to further studies in order to evaluate the possibility of reoviruses as an alternative for cancer treatment.

There are three different reovirus serotypes: type one Lang, type two Jones, and type three Abney and Dearing[ 44 ]. Among them, the T3D is the most widely studied as a possible therapeutic for cancer treatment and is also known as Reolysin[ 46 ]. Furthermore, reoviruses are dependent on a mutation in the ras gene in order to replicate properly in the tumor cells[ 47 ], a fact that limits its use, given that only approximately 30% of the human tumors have these mutations. However, the Ras pathway can be activated by some elements, which means that more types of cancer can be subjected to viral oncolytic therapy by reoviruses (up to 80%)[ 48 ].

Regarding the mechanism in which reoviruses replicate in tumor cells, the Ras pathway plays an important part, given that it inhibits protein kinase R and therefore enables viral protein synthesis[ 49 ]. Moreover, studies also show that the epidermal growth factor receptor, more specifically the tyrosine protein kinase signaling pathways, increases reovirus infection and viral peptide synthesis[ 50 ]. In addition, reovirus-resistant NIH 3T3 cells capable of being infected and enhance protein production when transfected with the gene encoding epidermal growth factor receptor or with the v-erbB oncogene are also documented[ 51 ]. Thereby, these works on reoviruses clarified their possible use in oncolytic therapy, given that they are also non-pathogenic in humans, which makes it an attractive option.

The main mechanism of tumor lysis by reoviruses is virus-induced apoptosis, along with the immunomodulatory characteristics of the virus. The viral capsid proteins are able to activate an apoptotic pathway in the tumor cells through release into the cytosol of cytochrome c and smac/DIABLO from the mitochondria[ 52 ]. In regard to the immune response, once the reoviruses start protein synthesis, there is a secretion of proinflammatory cytokines and chemokines through PAMPs and DAMPs, which eases the generation of an adaptive antitumor immune response[ 15 , 53 ]. Then, cytotoxic TCD8 cells recognize the reovirus antigens and lyse the cells, along with a maturation of dendritic cells[ 54 ], consequent activation of natural killer cells, and further cytotoxicity[ 55 ].

Herpes simplex virus type I : The herpes simplex virus-1 (HSV-1) is a double-stranded DNA virus with a large genome of 150kb encoding for 70 or more genes that belongs to the alpha-herpesviruses subfamily[ 56 , 57 ]. Its large genome is very important, given that it can be easily modified in order to improve oncolytic properties and safety for the patient[ 56 ]. Unlike the reoviruses, HSV-1 is pathogenic to humans and can cause infections of the mucosa or skin and central nervous infections, which reveals the need of deletions and insertions of additional transgenes in order to produce a viable oncolytic virus therapy[ 58 ].

In that context, a large number of oncolytic HSVs-1 have been developed and tested, with good outcomes, and among them the Talimogene Laherparepvec (T-VEC) is approved by the Food and Drug Administration[ 59 , 60 ]. T-VEC is one of the most studied HSV-1 oncolytic virus; it is created through deletion of γ34.5 and ICP47 and insertion of GM-CSF to inactivate neurovirulence factors and enhance the virus replication and immunogenicity[ 61 , 62 ]. It was also found possible to link HSV-1 to the ras signaling pathway in order to provide viral replication[ 63 ].

The mechanism of action of these viruses, especially T-VEC, is dual. The first aim is to perform direct tumor cell killing in which the viruses are able to enter the tumor environment, normally by local injection, and then start replication and consequent lysis of the infected tumor cell, release of tumor antigens, and local immune response[ 64 ]. In addition, the GM-CSF expression enables an accurate migration and maturation of dendritic cells to the environment and further antigen presentation to CD4+ and CD8+, which are capable of reaching distant metastases[ 65 , 66 ]. Studies also demonstrate that interferon response increases PD-L1 expression, and consequent T cell infiltration in the tumor environment is also possible[ 66 , 67 ]. Table ​ Table3 3 lists some genetic modifications in HSV-1 and impacts in the oncolytic action.

Genetic modifications in the herpes simplex virus-1

GM-CSF: Granulocyte-macrophage colony-stimulating factor; HSV-1: Herpes simplex virus 1; LAT: Latency-associated transcript; T-VEC: Talimogene laherparepvec; TK: Thymidine kinase.

CLINICAL USES

Pancreatic cancer.

Worldwide, the occurrence of pancreatic cancer is low, and the disease is not recommended for screening by the World Health Organization[ 68 ]. The survival rate of pancreatic ductal adenocarcinoma, responsible for 95% of pancreatic cancers[ 69 ], is 6% in 5 years[ 70 ], and the only potential cure for pancreatic ductal adenocarcinoma (duodenopancreatectomy) does not offer a big change in mortality[ 69 ].

Reolysin ® (Oncolytics Biotech Inc., Calgary, AB, Canada) is the name of a reovirus that is in a Phase II clinical trial in pancreatic cancer[ 71 ]. The studies are not yet conclusive. However, intraperitoneal administration of reovirus has been shown to be effective and safe in the control of peritoneal metastases in hamsters with pancreatic ductal adenocarcinoma carcinomatosis[ 72 ].

Measles viruses depend on overexpression of CD46, a viral entry receptor also found in many cancer cells[ 73 ]. In a previous study, a modified measles virus showed oncolytic activity in pancreatic tumor xenografts in mice with tumor regression and increased survival[ 74 ]. In another study, the virus was modified to target prostate stem cell antigen, which is a protein expressed in pancreatic cancer and was armed with the drug purine nucleoside phosphorylase. The authors concluded that viral therapy demonstrated antitumor activity in immunocompromised mice[ 75 ].

A study using H-1PV, a parvovirus, associated with gemcitabine in mice showed a reduction in tumor growth, in addition to increased survival and absence of metastases in imaging studies[ 76 ]. In another previous study using parvovirus, the infection increased natural killer-mediated cell death in pancreatic ductal adenocarcinoma[ 77 ]. However, many studies still need to be done to obtain a conclusive answer since current studies only suggest the viral oncolytic action of parvoviruses[ 76 ]. However, the myxoma virus demonstrated in vitro lysis of pancreatic ductal adenocarcinoma cells[ 78 ] and prolonged the survival of mice, especially when the therapy was combined with gemcitabine[ 79 ].

Adenoviruses are the main viral vectors used to treat cancer, as they are able to bind to a target cell receptor with great affinity[ 80 ]. This great affinity is due to the possibility of building the ideal selectivity using two techniques: excluding viral genes necessary for replication in normal cells and introducing fundamental proteins accompanied by specific tumor promoters[ 81 ]. In preclinical tests, ONYX-15, an adenovirus, had a deletion mutation of the E1B gene and showed increased survival and antitumor efficacy in murine animals[ 82 ], in addition to showing viability and tolerability when combined with gemcitabine. However, its development was interrupted due to its limited clinical activity[ 83 ]. The LOAd703 virus, a parvovirus with the deleted E1A gene, has shown that it can change the tumor microenvironment from immunosuppressive to immunocompetent[ 84 ]. Tests have also shown its ability to elicit immune responses by releasing tumor-associated antigens while positively regulating favorable chemokines as well as dendritic cells[ 85 ].

HSVs are recognized for infecting and killing tumor cells quickly[ 86 ]. In addition, HSV has exhibited strong tumor reactivity mediated by T cells, indirectly causing an immune response to cancer[ 87 ]. In 1999, preclinical data showed that G207, an HSV-1 virus with gene deletions and inactivations, lysed pancreatic ductal adenocarcinoma cells in vitro [ 88 ] and induced complete tumor eradication by 25% when injected into mice xenograft tumors[ 89 ]. L1BR1, an HSV-2 with deletion of the US3 gene, replicated in pancreatic ductal adenocarcinoma cells and induced apoptosis cytolysis, especially when combined with 5-fluorouracil and cisplatin[ 90 ]. In a phase I study, HF10, a natural HSV-1 mutant, was injected into pancreatic tumors in 6 patients. Biopsies revealed a greater number of infiltrating CD4+ and CD8+ lymphocytes. In addition, an objective response was observed in 1 patient, while disease stabilized in 3 patients, and in the remaining 2 cases there was disease progression[ 91 ]. Finally, two phase I trials were performed to test the safety of the intratumoral injection of T-VEC (OV HSV-1 with multiple deletions) and Orien X010 (OV hGM-CSF HSV-1 recombinants) in advanced pancreatic cancer patients[ 92 - 94 ]. However, unfortunately, the results have not yet been reported to the scientific community.

Melanoma is a potentially fatal malignant skin disease that continues to have greater incidences in the world, while the scenario of other tumors is the opposite[ 95 ]. The average risk of melanoma is 1 in 50 in several western countries[ 96 ] and is more frequent in light-skinned populations[ 97 ].

Regarding OV therapy, the vaccinia virus is a prototypical poxvirus with high clinical relevance, which can be easily attenuated by deleting virulence genes and inserting therapeutic genes[ 98 ]. Two phase I studies using JX-594, an OV vaccinia modified to activate local macrophages and dendritic cells[ 99 ], involved a total of 17 patients with unresectable cutaneous melanoma. The studies concluded that JX-594 replicated successfully in the tumor microenvironment, led to local oncolysis, and that increasing doses of JX-594 were safe and effective[ 100 , 101 ]. In two other similar phase I clinical trials, they used the vaccinia virus, which encodes B7.1 T cell co-stimulating molecules[ 102 ], in 25 patients with unresectable melanoma. As a result of these tests, the rate of complete objective response was 20% with limited toxicity and low-grade reactions[ 102 , 103 ].

The herpes simplex virus is an attractive option for OV in melanoma since the large genome has several non-essential genes that can be deleted in order to reduce pathogenicity and insert genes of interest[ 104 ]. Currently, T-VEC is the first oncolytic virus approved by the United States Food and Drug Administration for melanoma cancer therapy[ 105 ]. Phase I, II, and III clinical trials were concluded with positive results from the use of T-VEC in the treatment of melanoma[ 106 - 108 ]. Biopsies of injected lesions were performed in phase I and showed significant tumor necrosis caused by T-VEC[ 107 ]. In phase II, the overall objective response rate was 26% with a 1 year survival rate for all patients of 58% and mild side effects in 85% of patients[ 107 ]. Finally, in phase III, the objective response rate for the T-VEC arm remained at 26% with 11% complete responses, but unfortunately the final survival data are not available[ 108 ]. Even so, this was the first randomized clinical trial to reveal beneficial therapeutic use of OV for patients with advanced or unresectable melanoma[ 104 ].

HF10, a spontaneously mutated strain of HSV-1 with a deletion mutation in some viral genes[ 109 ], was used in an in vitro study that revealed that murine and human melanoma tumor cells had relevant cytolytic effects after HF10 infection[ 110 ]. In that same study, immunocompetent mice with advanced melanomas received HF10 intratumorally. Tumor growth was reduced in injected and non-injected tumors, which suggests direct oncolysis and induction of a systemic antitumor immune reaction[ 110 ]. HF10 was associated with dacarbazine to assess the oncolytic efficacy of the virus in mice prepared with subcutaneous melanoma models. The combined treatment of dacarbazine with HF10 showed a very fast and strong cytotoxic effect compared to monotherapy since a robust systemic antitumor immune response was induced and prolonged survival[ 111 ].

Other viruses with fewer highlights have been tested and have shown good results. Coxsackievirus A21 demonstrated in preclinical studies oncolytic activity in melanoma cells, maintaining tolerability and low viral pathogenicity[ 112 ]. CVA21, a commercial version of coxsackievirus A21, was studied clinically in phase I and II in patients with advanced and unresectable melanoma who received the virus intratumorally for 15 wk. As a result of these trials, the treatment was generally well tolerated with low-grade reactions, being able to observe complete therapeutic responses and an acceptable safety profile[ 113 , 114 ]. Finally, a phase II trial evaluated the oncolytic action of Reolysin ® in 21 patients with metastatic melanoma who received intravenous injections[ 71 ]. All patients tolerated the injections well, and in 2 patients viral replication was evident when evaluating post-treatment biopsy samples from 13 patients. However, the study did not obtain observed objective responses nor did it achieve its primary efficacy objective, although the trial data support the use of reovirus in combination with other therapies to treat malignant melanoma[ 71 ].

Breast cancer

Breast cancer (BC) is a multifactorial and heterogeneous disease in which the interaction between family history, lifestyle, and hormonal components has a fundamental role in its development[ 115 , 116 ]. Worldwide, the numbers of the disease are increasing, partly due to the increase in life expectancy of the population but also associated with the increase in early diagnosis techniques. Currently, 1 in 8 women have a chance of being diagnosed with BC in the world, making it the most common cancer among women[ 117 ].

There are prospects for treatment of more advanced forms of the disease since to date oncolytic virotherapy has demonstrated a wide variety of options for action at the cellular and molecular level[ 118 ]. Among the options currently most sought for this purpose, there are double-stranded DNA viruses that replicate and transcribe in the cell nucleus, without the integration of its genetic material with that of the host cell[ 118 ]. In addition, it is essential that OVs are extremely selective to replicate in cancer cells[ 15 ], a fact corroborated by tests that show the good tolerability and selectivity of genetically modified viruses for this purpose, such as the vaccinia virus[ 119 ]. Another important OV, adenovirus, one of the most studied for BC, is still controversial. Preclinical studies show efficacy in tumor reduction by inhibiting the growth of its cells in addition to controlling metastases in mice[ 118 ]; however, other phase I trials demonstrate low efficacy for BC either in monotherapy or in combination with other drugs[ 119 ]. In addition to these, T-VEC approved in the United States and Europe for use in some types of melanomas[ 120 ] has been clinically tested in BC and shows good tolerability by the patient as well as relative success in inducing tumor necrosis and immune response[ 119 , 121 ].

RNA viruses such as Pelareorep (Reolysin) have also been studied for BC[ 119 ]. Although inconclusive, the trials show that there is safety in its use, in addition to an efficiency in viral replication and in its induction of cell death[ 122 ]; however, they suggest that the administration of Pelareorep in combination with the drug paclitaxel is more effective when compared to its isolated use[ 123 ]. An important point of this virus is its optimized form of intravenous administration, which favors its development even more and extends its use when compared to most of the OVs that are still administered in clinical trials by intratumoral route[ 119 ]. Also very promising against BC is the marabá virus, a strain of rabdovirus. Its MG1 variant was developed to have a greater oncolytic action and also little replicative action in normal cells, achieving success in these objectives[ 118 ]. As for tumor control, trials have shown an important association of positive results in the use of MG1 for the prevention of metastasis in the preoperative period[ 124 ] as well as in the safety of its use and the possibility of having a good systemic efficiency[ 125 ].

Liver cancer

A highly malignant tumor type, liver cancer is still a major challenge to current medicine[ 126 ]. Its most common form is hepatocellular carcinoma (HCC)[ 126 , 127 ], which represents one of the six most prevalent and four most lethal types of cancer in the world[ 128 - 131 ]. Linked to this, HCC is attributed to an increase over the years[ 128 ], related to a high worldwide prevalence, concentrated mainly in underdeveloped countries[ 130 ]. The unfavorable numbers corroborate to a high rate of disease recurrence after conventional therapies currently used, with just over 10% of patients surviving after 5 years[ 129 ].

The literature shows OVs as promising in the possibility of overcoming HCC, especially in more advanced stages, in a safe manner and with the least possible chance of recurrence[ 129 , 131 ]. One of the most widely used is adenovirus, which shares a relevant tropism for liver cells[ 128 ]. Among this type of virus, there are several lines of studies with particular modifications aiming at a better viral adaptation to the obstacles found in tumor cells. One of them is the Ad5 viral vector integrated with the GP73 and SphK1-shRNA promoters[ 130 ], in which through preclinical tests it was able to induce cell apoptosis and inhibit tumor expansion considerably, improving the survival of mice[ 131 ]. The adenovirus ZD55 vector was modified to overcome the high resistance of HCC cells to tumor necrosis factor-related apoptosis ligand and successfully managed to reduce the tumor size by associating ZD55-tumor necrosis factor-related apoptosis ligand with ZD55-Smac, a variant that has a second mitochondrial caspase activator in its constitution[ 128 ].

The vaccinia virus has also been studied for HCC. The JX-594 variant has been proven safe and effective through preclinical studies in rabbits by eradicating lung metastases and liver tumors in these animals[ 126 , 128 ]. In addition to this, the vaccinia virus may also be associated with cytokines, such as recombinant VV-IL-37, which with interleukin 37 associated with its genome also inhibited liver tumor growth[ 130 ]. Among the therapeutic options, it is also worth highlighting the findings in trials using HSV. A study using mice developed Ld0-GFP, a more selective and more oncolytic vector for liver cells, which has safely demonstrated an important potential in the induction of cell apoptosis and in the release of DAMPs related to immunogenic cell death[ 129 ].

Glioblastoma

Glioblastoma is the most common malignant primary brain tumor in adults, with a median age of approximately 55 to 60 years and has a 10% survival rate after 5 years[ 6 ], even with important advances in recent years in cancer therapy. Thus, oncolytic therapy has been highlighted in the treatment of glioblastoma, once it kills tumor cells via direct oncolysis and via stimulation of antitumor immune response[ 132 ].

Regarding the use of OVs, studies have shown its use with combined therapy and monotherapy. A research conducted at clinicaltrials.gov, Martikainen et al [ 133 ] found more than fifteen clinical studies at different stages. A phase II study, using the modified DNX2440 adenovirus, combining oncolytic virus with tumor-targeting immune checkpoint modulators, demonstrated that the virus was able to specifically increase T cell activation, facilitating tumor recognition. In other studies, HSV (phase I), vaccinia virus (phase I/II), poliovirus (phase I/Ib), parvovirus H-1PV (phase I/II), and unmodified human reovirus were also used[ 134 - 137 ]. The study using attenuated (Sabin) poliovirus with internal ribosomal entry site from human rhinovirus 2 was applied to 61 patients over a period of 5 years with the result of increasing their patients’ survival rate by 24 and 36 mo compared with the rate among historical controls. On the other hand, the study with unmodified rat parvovirus indicated that H-1PV treatment was safe and well tolerated. It showed favorable pharmacokinetics, induced antibody formation in a dose-dependent manner, and triggered specific T cell responses. There was an increase in survival compared to recent studies. Furthermore, researchers who used unmodified human reovirus reported that 10 of the 12 patients had tumor progression and 1 had stabilized, while the median survival was 21 wk. Finally, the preclinical study involving HSV-1 and rats used the modern approach of viral redirection with IL-12, resulting in increased overall survival and complete tumor elimination in 30% of the animals.

Prostate cancer is the most common cancer among men and the second type of cancer that kills men the most in Western countries[ 138 ]. In view of the therapies currently available, the OVs are an attractive way of treating prostate cancer, either as monotherapy or in combination with other immunotherapies (for example, anti-programmed cell death protein 1 and anti-PD-L1 inhibitors)[ 139 ]. This is due to the immunological events induced by the administration of OVs in cancer-bearing animals that bring down multiple tumor immune evasion mechanisms and induce strong, multiclonal, and protective anti-prostate cancer immunity. The effect of OVs on prostate cancer occurs because of abnormalities in antiviral defense pathways, including those attributed to impaired tyrosine-protein kinase Janus kinase, a signal transducer and activator of transcription signaling.

To date, there are several clinical trials in phase I and II using adenovirus, reovirus, HSV-1, vaccinia virus, fowl pox virus, and Sendai virus[ 140 ]. Among the studies with adenovirus, one was able to insert mk5 (the mutational kringle5 of human plasminogen) into a DD3-promoted (differential display code 3) oncolytic adenovirus, showing that mK5 has been proven to be able to inhibit the tumor angiogenesis and inhibit cell proliferation[ 141 ]. Currently, a number of Ad5-CD/TK OVs have been developed and tested as a therapeutic for prostate cancer. These viruses provide two suicide genes, cytosine deaminase and HSV-1 TK, to tumor cells. Studies using a reovirus in patients with metastatic castration-resistant prostate cancer, on the other hand, showed an increase in the secretion of inflammatory cytokines[ 138 ].

Colorectal cancer

Colorectal cancer is the third most common cancer in the United States and the second leading cause of cancer-associated mortality[ 142 ]. There is currently no effective treatment for this type of cancer, so OVs can be an interesting option in this way. Heavily pretreated colorectal cancer patients were treated with the oncolytic vaccinia virus alone or combined, by increasing the expression of GM-CSF (a hematopoietic growth factor) and reached stable disease in 67% of patients[ 143 , 144 ]. Another study using oncolytic HSV2 performed an in vitro and in vivo analysis. In the first, oncolytic HSV2 effectively inhibited the growth of CT-26 cells. In the second, hepatic metastasis was reduced in mice models with xenograft tumor[ 145 ].

FUTURE CHALLENGES AND PERSPECTIVES

A wide variety of OVs are going through studies in phase I/II clinical trials or in preclinical cancer models[ 2 , 146 ]. According to clinicaltrials.gov, there are currently 114 clinical trials listed at the time of this writing showing considerable progress in this field. Despite all the advances, some limitations still have to be surpassed to enhance OV-based immunotherapy[ 37 , 119 , 147 ]. Thus, to overcome these challenges, research scientists are creating new strategies, which will be presented below.

Choosing the optimal OV species

As aforementioned, a range of virus species has been developed as OVs recently. It is essential to comprehend the exclusive biological aspects to establish the most relevant antitumor oncolytic virotherapy, considering that distinct kinds of viruses have different sizes, genetic materials, shapes, and pathogenicity[ 148 ]. First, the size of the virus must be considered; larger viruses are more suitable for the therapeutic gene insertion, but they are less inclined to infiltrate the physical barriers, whereas smaller viruses can penetrate and spread throughout the tumor more easily, though they are not as susceptible for genetic administration[ 148 ]. In addition, the viral genome is important; RNA viruses replicate faster than DNA viruses and are able to kill tumor cells because they do it in the cytoplasm and do not have to reach the nuclei of the target cells[ 149 ]. Nevertheless, they have shown fewer tumor-selective properties due to the same reason[ 150 ]. Likewise, the existence of a viral capsid is also a crucial factor in OV selection because enveloped viruses are less oncolytic and are more likely to be eliminated by the host immune system[ 149 ].

Therefore, during the past decade, some improvements have emerged in the area, such as capsid development, genome engineering, and chemical modifications[ 151 ]. The capsid can be altered to improve the binding between the virus and the entry receptors from the target cell. For example, researchers have noticed that genetically inserting protein domains or peptides into the viral capsid can benefit transduction efficacy in some cells and improve the attachment of the OVs to target tumor cells membranes, boosting viral tropism, and internalization[ 151 - 153 ]. Furthermore, viral cytotoxicity needs to be considered since the high capacity to generate cell injuries can decrease viral replication rates and consequently interfere in the effectiveness of therapy[ 154 ]. Meanwhile, all of those strategies still have limitations and need to be improved.

Effective delivery methods

Finding an ideal route for OV administration still constitutes one of the major challenging issues in virotherapy[ 60 ]. The two leading delivery platforms include local intratumoral, which the OVs are injected directly into the tumor site, and systemic method (intravenous or intraperitoneal)[ 4 , 55 ]. Local intratumoral is the most common delivery route in preclinical or clinical trials due to its safety and to decrease the chance that preceding circulating antibodies might overcome the virus before it reaches its target[ 2 , 155 , 156 ]. However, this platform cannot be utilized for inaccessible or multifocal tumors, such as pancreatic or brain tumors, so it is not always a viable option[ 157 ]. On the other hand, the systemic injection is, theoretically, an ideal delivery method, because of the broad distribution of viruses, allowing the OVs to reach not only primary but also metastatic tumors, and it is relatively non-invasive and highly repeatable[ 155 , 157 ]. Nonetheless, its bioavailability and efficiency at the moment is unsatisfactory, and the viral particles in this route do not specifically target cancer because they can be rapidly sequestered and degraded by the host immune system before they reach the tumor[ 158 ].

In this way, several strategies have been studied to overcome these hurdles. For example, capsid modifications have been explored as a way to deliver OVs to tumor sites, like the changing of the viral envelope by polyethylene glycol polymers that prevent its recognition by macrophages[ 151 , 157 , 159 ]. Thus, considerable new approaches such as the use of nanoparticles, complex viral particle ligands, liposomes, polymeric particles, and immunomodulatory agents have been used and designed[ 160 - 163 ]. Another hopeful strategy is the utilization of ultrasound image guiding and magnetic drug-targeting systems[ 164 - 166 ]. These are all different kinds of approaches for improving the delivery methods.

Immune response

The immune response is an obstacle capable of preventing the effectiveness of OVs, given that it can limit infection and viral replication, whether by the specific immunity from viral infections or by pre-existing immune memory[ 167 , 168 ]. There are many cases in which antiviral immunity already exists from previous infections or vaccinations since many of the OVs used in anticancer therapy are originally pathogenic to humans[ 159 , 169 ]. Besides that, the excessive administration of OVs can induce antiviral immunity that eliminates it more quickly than supposed[ 159 ]. The presence of coagulation factors FIX, FX, and complement protein C4BP and the large number of immune cells infiltrated into the cancerous stem cells impair selective viral replication as well[ 149 , 170 ].

To overcome such problems, new treatment strategies were developed and showed promising results as genetic manipulation of OVs, cytokines, nanoparticles, complex viral particles binders, immunomodulatory agents, use of decoy viruses for sequestering pre-existing antibodies, and multiple administration of different serotypes[ 120 , 168 ]. However, it is relevant to emphasize that viral immunity can be beneficial in some cases by recruiting immune cells for tumor microenvironment (TME) and reversing the immunosuppressive TME. Therefore, there must be an adjustment in the balance between OV-induced antitumor immunity and antiviral immunity[ 147 , 169 , 171 ].

Physical barriers

Another major challenge that OVs need to overcome is physical barriers, as viruses must pass through the endothelial layer to reach target cells. Studies have identified several physical barriers that limit effectiveness, such as chemotherapeutic agents, monoclonal antibodies, antitumor immune cells, and genetic therapies[ 149 , 172 , 173 ]. Furthermore, abnormal lymphatic networks and epithelial cell tumors are protected by extracellular matrix, which results in interstitial pressure and may impair the ability of OVs to spread themselves throughout the tumor mass, negating its effectiveness[ 174 , 175 ].

Therefore, strategies to achieve efficient penetration and dissemination of OVs are highly necessary for significant improvements in this therapeutic modality[ 176 ]. To increase the viral spread, oncolytic adenovirus genetically modified to express molecules such as relaxin and hyaluronidase were generated in order to stop angiogenesis of the extracellular matrix and have shown promising preclinical results[ 174 ]. An intravenous administration of the OVs can bring numerous benefits for the vascularization of the tumor, being able to be superior to intratumoral injections[ 176 ]. Studies show efficiency in the spread of OVs in solid tumors through changes in the viral envelope or by increasing the diffuse transport of the virus through changes in the interstitial space[ 177 ]. These data provide strong evidence of the significant antitumor effects of the therapy.

Clinical use of OVs allies to other therapies

Since OVs showed limited efficacy in monotherapy, the combination of immunotherapy drugs and virotherapy has become a potential direction and appealing choice[ 158 , 178 ]. In this way, some preclinical studies in animal models and early clinical trials have confirmed the therapeutic responses increased with combination approaches, showing considerable response rates and tolerable safety profiles[ 120 , 179 ]. The following sections discuss these diverse combination strategies.

Combination with chemotherapy

The combination of virotherapy with chemotherapy agents is a promising approach. For example, adenovirus combined with chemotherapeutic agents such as cisplatin, 5-fluorouracil, doxorubicin, temozolomide, irinotecan, and paclitaxel has successful results and enhanced antitumor effects compared to the response rate of the virus alone[ 179 - 181 ]. Concomitantly, a combination strategy also showed less risks and higher safety, extending the patient’s survival[ 182 ]. Likewise, vaccinia virus combined with paclitaxel also revealed a harmonious effect[ 183 ]. In some models, the combination of sorafenib and vaccinia virus demonstrated good antitumor results, while patient trials showed remarkable safety and clinical response, and it has been approved for use in kidney, liver, and thyroid cancers[ 184 ].

Combination with radiotherapy

Radiotherapy combined with OVs has shown potential effects in cancer treatment[ 185 - 187 ]. Initially, the propitious result was observed in studies with oncolytic HSV[ 188 - 190 ]. In addition, the forceful combination effects can also be observed in radiotherapy and vaccinia virus. For example, a study reported that VACV-scAb-vascular endothelial growth factor was able to boost the radiation therapy’s sensitivity of tumor locations, increasing the antitumor response[ 191 ].

Combination therapy with adoptive cell therapy

Another promising strategy is the combination of OVs and adoptive cell therapy since OVs can kill cancer cells specifically and have the potential of turning the TME into an immunostimulatory environment that is susceptible to T cell entry and activation[ 192 ]. A recombinant oncolytic adenovirus, OAd-TNF-a-IL-2 combined with meso-chimeric antigen receptor T cells in an animal model of pancreatic ductal adenocarcinoma caused considerably better tumor regression and expanded the antitumor effectiveness of chimeric antigen receptor T cells[ 193 ]. Furthermore, a preclinical trial of this combination approach utilizing GD2-chimeric antigen receptor T cells and a recombinant oncolytic adenovirus in a mouse model revealed substantial elevated overall survival of mice as with both monotherapy ways[ 194 ]

Combination therapy with OVs and immune checkpoint inhibitors

One of the most common strategies to increase the effectiveness of OVs is to combine them with ICIs as the combination of the two therapies relieves the tumor immunosuppressive environment. The infection caused by OVs triggers an anticancer immune response, increasing the effectiveness of ICIs, which in the process interrupt the ligand-receptor interaction of cancer cells exposing T cells to attack[ 169 , 194 , 195 ]. In short, the objective of this combination is to make the local microenvironment more conducive to the proper functioning of ICIs through infections caused by OVs[ 195 - 197 ]. This synergistic relationship has led to the development of several studies with promising results.

For example, a phase II study (clinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02978625","term_id":"NCT02978625"}} NCT02978625 ) studied how biological therapy T-VEC and the immunotherapy with monoclonal antibodies nivolumab worked in 68 patients with lymphoma who have not responded to treatment or non-melanoma skin cancers that have spread to other parts of the body or have not responded to treatment. In addition, the combination of ICIs with various OVs, such as vaccinia virus, coxsackievirus, adenovirus, marabá virus, reovirus, and vesicular stomatitis virus, is being evaluated in different phase I or phase II clinical trials[ 167 , 198 ]. Thus, new treatment options through this combination continue to be awaited with expectations of promising paths.

Combination therapy with OVs and bispecific T cell engagers

In recent decades, there has been great clinical progress in immunotherapy with bispecific antibodies and effective therapeutic applications[ 199 ]. By definition, bispecific T cell engagers (BiTEs) are proteins that, through DNA recombination, form bispecific antibodies with two variable fragments of single chain antibodies, one directed to a cell surface molecule in T cells (for example, CD3) and the other targeting antigens on the surface of malignant cells[ 172 , 200 ]. BiTE-mediated interaction triggers the formation of immune synapses, which ultimately result in tumor specific cell death and release of effector Th1 cytokines[ 201 ]. However, BiTEs have low penetration in solid tumors, in addition to the risk of toxicity in hematological cancers[ 172 , 200 ]. In this sense, the combination of BiTEs and OVs is considered in order to increase therapeutic efficacy since OVs are able to selectively replicate and infect malignant cells, thus alleviating the immunosuppressive state of the TME[ 172 , 201 ].

Currently, several BiTEs delivered by OVs have been tested on several types of hematological and solid tumors reported by preclinical research, and promising tests were obtained with a BiTE that recognizes fibroblasts associated with cancer ( via fibroblast activation protein)[ 202 ]. In addition, preclinical studies also provided evidence of the effectiveness of OVs in combating the side effects of therapy with BiTEs through the redirection of T cells, in addition to improving antitumor activity[ 203 ]. Such efforts should lead to the development of new anticancer agents as it is believed that this combination is powerful to address unmet clinical needs[ 199 ].

Biosafety on oncolytic virotherapy

Although OV therapy has shown potential to be a safe treatment for cancer patients, some biosafety issues in vivo still remain a concern as a treatment strategy. Primarily, some adverse events were associated with this therapy[ 14 ]. A few symptoms, such as mild flu-like syndromes[ 204 , 205 ], local reactions commonly manifested as pain, rash, peripheral edema, and erythema, are the most common events linked to the treatment[ 124 , 206 ]. Some of them disappeared without intervention after a few days or with the administration of nonsteroidal anti-inflammatory drugs during the treatment course[ 4 , 207 ]. In addition, other common adverse events, like leukopenia, liver dysfunction, anemia, lymphopenia and more, were noticed in the trials of HSV, reovirus, and adenovirus[ 208 , 209 ]. Besides this, few OV therapies have caused severe adverse reactions that brought harm to patients’ health[ 162 , 210 - 212 ], and they have been manageable and rarely caused a severe impact on the patients or threatened their lives[ 162 , 213 ]

Moreover, the transmission and shedding of OVs during the treatment is also a potential safety issue. During the therapy, viruses such as T-VEC, Ad5- Δ24-RGD, HSV, adenovirus, pox, and reovirus, can be transmitted to people in close contact with the patient, such as the family and health care staff who are more likely to be exposed to the patient’s fluids, such as saliva or urine, or be shed to other parts of the patient’s body[ 214 - 216 ]. Another challenge in the biosafety of the use of OVs is the application of the treatment in specific populations, given that the studies in this area are currently limited[ 14 ]. Therefore, in order to reduce risks, the viruses observed are highly attenuated, in addition to being of the utmost importance that the health professionals who administer OVs carefully follow the safety standards for the procedures[ 215 , 216 ]. On the other hand, the trials and preclinical studies of several viruses, like the T-VEC, HSV-1, and H-1PV indicate that pregnant women and people with low immunity should avoid using them[ 214 , 217 ].

Lastly, aiming to improve the biosafety of oncolytic viral therapy and decrease its side effects, the use of viruses that do not present pathogenicity to humans are being evaluated. H-1PV, for example, demonstrated no inducement of the production of specific antibodies when inoculated in humans, which means little chance of generating an active infection. Nevertheless, the virus has shown specificity to the tumor cells[ 218 ]. Furthermore, the recombinant therapies between different OVs, such as adenovirus and parvovirus, have shown satisfactory results in terms of biosafety since the synergistic action generated from the viral specificities, such as the infectivity of adenoviruses to the tumor cells and the lack of harmfulness of parvovirus to the normal cells, contributes to greater therapeutic efficacy and reduction of collateral damage[ 14 ].

OVs emerge as a way of bypassing the immune evasion mechanisms of the tumor, aiming to improve the clinical condition of patients through the stimulation of the host immune system or direct lysis of abnormal cells. The modern techniques of genetic engineering have made it possible to improve the construction of OVs, increasing the safety and the efficiency, targeting the virus to the tumor, and decreasing the adverse effects of their use. Furthermore, it is possible to observe significant effects of the clinical use of OVs, whether in single or combination therapy, to the treatment of tumors. Therefore, upgrading antitumor therapies and consequently improving patient prognosis with contributions from the areas of molecular biology, structural biology, immunology, genomics, and bioinformatics lays a solid foundation for future clinical success of OVs.

Conflict-of-interest statement: Authors declare there are no conflicts of interests in this manuscript.

Manuscript source: Invited manuscript

Peer-review started: March 10, 2021

First decision: May 5, 2021

Article in press: August 9, 2021

Specialty type: Oncology

Country/Territory of origin: Brazil

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P-Reviewer: Chung YH S-Editor: Wang JL L-Editor: Filipodia P-Editor: Xing YX

Contributor Information

Jonathan Santos Apolonio, Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil.

Vinícius Lima de Souza Gonçalves, Universidade Estadual do Sudoeste da Bahia, Campus Vitória da Conquista, Vitória da Conquista 45083-900, Bahia, Brazil.

Maria Luísa Cordeiro Santos, Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil.

Marcel Silva Luz, Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil.

João Victor Silva Souza, Universidade Estadual do Sudoeste da Bahia, Campus Vitória da Conquista, Vitória da Conquista 45083-900, Bahia, Brazil.

Samuel Luca Rocha Pinheiro, Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil.

Wedja Rafaela de Souza, Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil.

Matheus Sande Loureiro, Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil.

Fabrício Freire de Melo, Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil. rb.moc.oohay@olemerierf .