Mechanisms of SARS-CoV-2 Transmission and Pathogenesis
Authors: Andrew G. Harrison, Tao Lin, Penghua Wang
Journal: Trends in Immunology (2020)

The emergence of SARS-CoV-2 from China and the rapidity of a worldwide pandemic has promoted global collaboration, built on a body of work established from previous SARS-CoV and MERS-CoV outbreaks. These past experiences have aided the swiftness by which the research community has responded with an astonishing body of work.SARS-CoV-2 is a novel virus in the Betacoronavirus genus and exhibits similarities to SARS-CoV in genome structure, tissue tropism, and viral pathogenesis. Yet, SARS-CoV-2 appears to be more transmissible and the diversity of immune responses are poorly understood.Highly pathogenic coronaviruses display potent interferon (IFN) antagonism, which is evident in cases of severe COVID-19 with reduced IFN signaling, and an overaggressive immune response compounded by heightened cytokines/chemokines.Animal models for SARS-CoV-2 recapitulate important aspects of human COVID-19 that are essential for evaluating current and prospective antiviral therapeutics and vaccine candidates. The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) marks the third highly pathogenic coronavirus to spill over into the human population. SARS-CoV-2 is highly transmissible with a broad tissue tropism that is likely perpetuating the pandemic. However, important questions remain regarding its transmissibility and pathogenesis. In this review, we summarize current SARS-CoV-2 research, with an emphasis on transmission, tissue tropism, viral pathogenesis, and immune antagonism. We further present advances in animal models that are important for understanding the pathogenesis of SARS-CoV-2, vaccine development, and therapeutic testing. When necessary, comparisons are made from studies with SARS to provide further perspectives on coronavirus infectious disease 2019 (COVID-19), as well as draw inferences for future investigations. The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) marks the third highly pathogenic coronavirus to spill over into the human population. SARS-CoV-2 is highly transmissible with a broad tissue tropism that is likely perpetuating the pandemic. However, important questions remain regarding its transmissibility and pathogenesis. In this review, we summarize current SARS-CoV-2 research, with an emphasis on transmission, tissue tropism, viral pathogenesis, and immune antagonism. We further present advances in animal models that are important for understanding the pathogenesis of SARS-CoV-2, vaccine development, and therapeutic testing. When necessary, comparisons are made from studies with SARS to provide further perspectives on coronavirus infectious disease 2019 (COVID-19), as well as draw inferences for future investigations. CoVs have caused three large-scale outbreaks over the past two decades: severe acute respiratory syndrome (SARS), Middle Eastern respiratory syndrome (MERS), and now COVID-19. The origin of the COVID-19 pandemic was traced back to a cluster of pneumonia cases connected to a wet seafood market in Wuhan City, Hubei Province, China [1.Zhou P. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (3510) Google Scholar]. Following the likely spillover of a zoonotic disease (see Glossary), further work confirmed the etiological agent to be a novel Betacoronavirus related to SARS-CoV [1.Zhou P. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (3510) Google Scholar,2.Peiris J. et al.Coronavirus as a possible cause of severe acute respiratory syndrome.Lancet. 2003; 361: 1319-1325Abstract Full Text Full Text PDF PubMed Scopus (1895) Google Scholar]. The first patients developed symptoms on December 1, 2019 after which rapid human-to-human transmission and intercontinental spread later ensued, being declared a pandemic by the WHO in March 2020 [3.Huang C. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (8744) Google Scholar]. Since then, ~35 million people have been infected with SARS-CoV-2, with >1 million deaths in 235 countries, areas, or territories [4.WHO Coronavirus Disease (COVID-19) Pandemic. WHO, 2020Google Scholar]. Although SARS-CoV-2 appears to be less lethal than SARS-CoV or MERS-CoV, its transmissibility is higher. To find solutions to contain this raging pandemic, global research efforts have been quickly mobilized, each day resulting in new advances in basic and clinical research, therapy, diagnosis, vaccine and drug development, as well as epidemiology. Here, we conduct a comprehensive review of the current state of COVID-19 research, with a principal focus on the mechanisms of transmission and pathogenesis of SARS-CoV-2 stemming from clinical and animal studies. CoVs of the family Coronaviridae are enveloped, positive-sense single-stranded RNA viruses [5.Gorbalenya A.E. et al.The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2.Nat. Microbiol. 2020; 5: 536-544Crossref PubMed Scopus (1033) Google Scholar]. All of the highly pathogenic CoVs, including SARS-CoV-2, belong to the Betacoronavirus genus, group 2 [5.Gorbalenya A.E. et al.The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2.Nat. Microbiol. 2020; 5: 536-544Crossref PubMed Scopus (1033) Google Scholar]. The SARS-CoV-2 genome sequence shares ~80% sequence identity with SARS-CoV and ~50% with MERS-CoV [1.Zhou P. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (3510) Google Scholar,6.Lu R. et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.Lancet. 2020; 395: 565-574Abstract Full Text Full Text PDF PubMed Scopus (2388) Google Scholar]. Its genome comprises 14 open reading frames (ORFs), two-thirds of which encode 16 nonstructural proteins (nsp 1–16) that make up the replicase complex [6.Lu R. et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.Lancet. 2020; 395: 565-574Abstract Full Text Full Text PDF PubMed Scopus (2388) Google Scholar,7.Zhang Y.Z. Holmes E.C. 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However, the S gene of SARS-CoV-2 is highly variable from SARS-CoV, sharing <75% nucleotide identity [1.Zhou P. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (3510) Google Scholar,6.Lu R. et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.Lancet. 2020; 395: 565-574Abstract Full Text Full Text PDF PubMed Scopus (2388) Google Scholar,9.Wu F. et al.A new coronavirus associated with human respiratory disease in China.Nature. 2020; 579: 265-269Crossref PubMed Scopus (1535) Google Scholar]. Spike has a receptor-binding domain (RBD) that mediates direct contact with a cellular receptor, angiotensin-converting enzyme 2 (ACE2), and an S1/S2 polybasic cleavage site that is proteolytically cleaved by cellular cathepsin L and the transmembrane protease serine 2 (TMPRSS2) (Figure 1) [1.Zhou P. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (3510) Google Scholar,9.Wu F. et al.A new coronavirus associated with human respiratory disease in China.Nature. 2020; 579: 265-269Crossref PubMed Scopus (1535) Google Scholar,10.Hoffmann M. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (2529) Google Scholar]. TMPRSS2 facilitates viral entry at the plasma membrane surface, whereas cathepsin L activates SARS-CoV-2 Spike in endosomes and can compensate for entry into cells that lack TMPRSS2 (Figure 1) [10.Hoffmann M. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (2529) Google Scholar]. Once the genome is released into the host cytosol, ORF1a and ORF1b are translated into viral replicase proteins, which are cleaved into individual nsps (via host and viral proteases: PLpro); these form the RNA-dependent RNA polymerase (nsp12 derived from ORF1b) [8.Perlman S. Netland J. Coronaviruses post-SARS: update on replication and pathogenesis.Nat. Rev. Microbiol. 2009; 7: 439-450Crossref PubMed Scopus (548) Google Scholar]. Here, the replicase components rearrange the endoplasmic reticulum (ER) into double-membrane vesicles (DMVs) that facilitate viral replication of genomic and subgenomic RNAs (sgRNA); the latter are translated into accessory and viral structural proteins that facilitate virus particle formation (Figure 1) [11.Snijder E.J. et al.Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex.J. Virol. 2006; 80: 5927-5940Crossref PubMed Scopus (234) Google Scholar,12.Wu H.-Y. Brian D.A. Subgenomic messenger RNA amplification in coronaviruses.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 12257-12262Crossref PubMed Scopus (0) Google Scholar]. The establishment of viral tropism depends on the susceptibility and permissiveness of a specific host cell. During the SARS epidemic, patients often presented with respiratory-like illnesses that progressed to severe pneumonia, observations mirroring the disease course of COVID-19, suggesting that the lung is the primary tropism of SARS-CoV-2 [13.Peiris J. et al.Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study.Lancet. 2003; 361: 1767-1772Abstract Full Text Full Text PDF PubMed Scopus (1356) Google Scholar]. 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Of note, the key mutations in the RBD of SARS-CoV-2 Spike make additional close contacts with ACE2, correlating with higher binding affinity and perhaps increased infectivity [1.Zhou P. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (3510) Google Scholar,14.Wrapp D. et al.Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.Science. 2020; 367: 1260-1263Crossref PubMed Scopus (4) Google Scholar,16.Yan R. et al.Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.Science. 2020; 367: 1444-1448Crossref PubMed Scopus (720) Google Scholar]. The presence of a unique furin cleavage site at the S1/S2 junction of SARS-CoV-2 Spike is also suspected to enhance human transmission events, although this remains to be further investigated [17.Shang J. et al.Cell entry mechanisms of SARS-CoV-2.Proc. Natl. Acad. Sci. U. S. 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