Assessment of SARS-CoV-2 replication in the context of other respiratory viruses
Authors: Jessica A Belser
Journal: The Lancet Respiratory Medicine (2020)

There is a wide diversity of respiratory pathogens associated with human infection and disease. To better understand the emergence of zoonotic viruses and the threat that these viruses pose to human health, it is often valuable to investigate newly identified viruses not in isolation, but rather in comparison, and in concert, with other related viruses. When assessing a newly identified virus, studies using genetically related strains, or viruses that share a similar cellular tropism, can facilitate identification of commonalities in numerous properties, such as binding, infectivity, and replication capacities. Comparative studies that identify how novel pathogens interact with host cells in ways that might contribute to viral pathogenicity, transmissibility, or tropism, are as valuable. During the early months of 2020, many studies have been initiated to better characterise severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—the virus that causes coronavirus disease 2019 (COVID-19). Some of the most valuable studies resulting from these research efforts are those that have evaluated this novel coronavirus alongside other contemporary coronaviruses associated with human infection (eg, severe acute respiratory syndrome coronavirus [SARS-CoV] and Middle East respiratory syndrome coronavirus [MERS-CoV]), and viruses from other families that have jumped species barriers to cause pandemics, or are considered to have pandemic potential (eg, the 2009 pandemic influenza H1N1 virus (H1N1pdm), or the highly pathogenic avian influenza H5N1 virus [H5N1]). Kenrie Hui and colleagues,1Hui KPY Cheung M-C Perera RAPM et al.Tropism of the novel coronavirus SARS-CoV-2 in human respiratory tract: an analysis in ex vivo and in vitro cultures.Lancet Respir Med. 2020; (published online May 7.)https://doi.org/10.1016/S2213-2600(20)30193-4Summary Full Text Full Text PDF PubMed Scopus (381) Google Scholar in The Lancet Respiratory Medicine, use exactly this approach, including all these viruses, to do a comparative analysis of virus tropism and induction of host responses in relevant human cell types and ex vivo explant cultures. The well characterised infection model developed by this group has aided past assessments of novel and emerging viruses, including A(H7N9) influenza viruses associated with human infection in 20132Chan MC Chan RW Chan LL et al.Tropism and innate host responses of a novel avian influenza A H7N9 virus: an analysis of ex-vivo and in-vitro cultures of the human respiratory tract.Lancet Respir Med. 2013; 1: 534-542Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar and A(H1N1) swine influenza viruses.3Chan RW Kang SS Yen HL et al.Tissue tropism of swine influenza viruses and reassortants in ex vivo cultures of the human respiratory tract and conjunctiva.J Virol. 2011; 85: 11581-11587Crossref PubMed Scopus (25) Google Scholar Hui and colleagues1Hui KPY Cheung M-C Perera RAPM et al.Tropism of the novel coronavirus SARS-CoV-2 in human respiratory tract: an analysis in ex vivo and in vitro cultures.Lancet Respir Med. 2020; (published online May 7.)https://doi.org/10.1016/S2213-2600(20)30193-4Summary Full Text Full Text PDF PubMed Scopus (381) Google Scholar show that SARS-CoV-2 binds to and replicates efficiently in ex vivo cultures of human bronchus and the lung, identifying cell type-specific parallels in virus replication compared with other transmissible viruses. Additionally, they show diminished induction of proinflammatory cytokines in human alveolar epithelial cells and peripheral blood monocyte-derived macrophages infected with SARS-CoV-2 and other coronaviruses compared with human and avian influenza viruses. Considering the wide clinical presentation of COVID-19 in humans,4WHOReport of the WHO-China joint mission on coronavirus disease 2019 (COVID-19).https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdfDate: 2020Date accessed: May 5, 2020Google Scholar inclusion of non-respiratory tissues in this study is especially valuable. Hui and colleagues show the susceptibility of human conjunctival explant cultures to SARS-CoV-2 infection (with higher levels of virus replication than SARS-CoV), a notable finding considering reports of ocular manifestations in some patients with confirmed COVID-19 infection, and detection of viral RNA in ocular swabs.5Wu P Duan F Luo C et al.Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei province, China.JAMA Ophthalmol. 2020; (published online March 31.)DOI:10.1001/jamaophthalmol.2020.1291Crossref Scopus (908) Google Scholar These observations support current recommendations by the US Centers for Disease Control and Prevention (US CDC) for personal protective equipment worn by health-care personnel to include both respiratory and eye protection.6US Centers for Disease Control and PreventionInterim infection prevention and control recommendations for patients with suspected or confirmed coronavirus disease 2019 (COVID-19) in healthcare settings.https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.htmlDate: 2020Date accessed: April 23, 2020Google Scholar Human colorectal carcinoma epithelial cells were also found to support virus replication with SARS-CoV-2, consistent with reports of detection of viral RNA in faecal samples and other tissues from the gastrointestinal tracts of patients with confirmed COVID-19, even in the absence of gastrointestinal symptoms.7Lin L Jiang X Zhang Z et al.Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection.Gut. 2020; (published online April 2.)DOI:10.1136/gutjnl-2020-321013Crossref Scopus (627) Google Scholar Most traditional risk assessments of emerging viruses study virus infection in previously uninfected cells, tissues, or serologically naive animal models, to investigate virus pathogenicity specifically attributable to the virus strain under evaluation. However, it is important to consider that humans are constantly exposed to a variety of viruses, with the potential for concurrent or subsequent infection with multiple pathogens. Interestingly, Hui and colleagues present preliminary data demonstrating that angiotensin-converting enzyme 2 (a receptor for SARS-CoV-2) mRNA was upregulated in human alveolar epithelial cells early after infection with human or avian influenza viruses. Although this finding will require additional evaluation, further study is warranted to better understand the dynamics of host susceptibility to SARS-CoV-2 in the context of infection with other pathogens, especially because coinfection with SARS-CoV-2 and influenza A virus has been reported.8Wu X Cai Y Huang X et al.Co-infection with SARS-CoV-2 and influenza A virus in patient with pneumonia, China.Emerg Infect Dis. 2020; (published online March 11.)DOI:10.3201/eid2606.200299Crossref Scopus (26) Google Scholar With a diversity of viruses in zoonotic reservoirs potentially capable of overcoming host range restrictions and acquiring the ability to spread in an immunologically naive population, the possible emergence of a new pandemic virus in humans is always on the horizon. There is a need for studies like those done by Hui and colleagues, which are inclusive of diverse viruses previously associated with human pandemics, and viruses believed to have the potential to do so, that use a range of relevant respiratory and non-respiratory tissue and cell types that might support virus replication following multiple exposure routes. These laboratory studies provide crucial context for interpretation of what makes each virus unique and how best to develop medical countermeasures to improve human health. I declare no competing interests. The findings and conclusions in this report are those of the author and do not necessarily represent the official position of the US CDC or the Agency for Toxic Substances and Disease Registry. Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro culturesThe conjunctival epithelium and conducting airways appear to be potential portals of infection for SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated similarly in the alveolar epithelium; SARS-CoV-2 replicated more extensively in the bronchus than SARS-CoV. These findings provide important insights into the transmissibility and pathogenesis of SARS-CoV-2 infection and differences with other respiratory pathogens. Full-Text PDF