Coronaviruses Causing Human Disease
Since the beginning of the 21st century, 3 beta coronaviruses have been found to cause severe respiratory illness in humans, including SARS-CoV, MERS-CoV (Middle Eastern respiratory syndrome coronavirus), and now SARS-CoV-2. Coronaviruses reside in many animal hosts and can adapt to different species, including humans. The proximal origin of SARS-CoV and SARS-CoV-2 is thought to be bats, while the reservoir host for MERS-CoV is the dromedary camel.1–3 Previous data suggest that in order for coronaviruses to exhibit efficient zoonotic transmission, the virus must undergo natural selection in an animal host (ie, intermediary species) such that it acquires features affording tropism to human tissue. To date, the intermediate host for SARS-CoV-2 is not known, however, a closely related coronavirus to SARS-CoV-2 has been identified in Malayan pangolins.4 Moreover, it remains to be established whether SARS-CoV-2 has acquired genomic changes within an intermediate animal host before the occurrence of human transmission, or whether a SARS-CoV-2 progenitor may have undergone genomic changes during undetected human-to-human transmission, ultimately resulting in the current pandemic.3
In humans, these coronaviruses gain entry into host cells by way of their transmembrane spike (S) GP (glycoprotein), which comprises an S1 and S2 subunit (Figure 1). The S1 subunit is responsible for binding to the host cell receptor, and the S2 subunit assists with viral and host cell fusion.1 While the MERS-CoV S GP binds to DPP-4 (dipeptidyl peptidase 4) expressed on epithelial tissue, both SARS-CoV-2 and SARS-CoV bind to human cells via the ACE-2 (angiotensin-converting enzyme 2) receptor.5 In addition to having different amino acid residues within the RBD (receptor-binding domain) of the S protein compared to SARS-CoV, another novel structural feature of SARS-CoV-2, is the presence of a polybasic furin cleavage site, at the junction of S1 and S2. Cleavage of the S protein by cellular proteases, including furin and TMPRSS-2 (transmembrane protease serine 2), is speculated to play an important role in the infectivity and host range of SARS-CoV-2, although its functional significance regarding how this feature may mediate SAR-CoV-2 transmissibility and pathogenicity is yet be fully elucidated.1 In the context of COVID-19-associated thrombosis, understanding how these structural differences of SARS-CoV-2 may relate to the prothrombotic phenotype of COVID-19 is likely to be of fundamental importance given the significantly higher rates of thrombosis observed in SARS-CoV-2, compared with SARS-CoV and MERS-CoV infections.
Figure 1.  Proposed mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, and coronavirus disease 2019 (COVID-19)-associated thrombosis. SARS-CoV-2 gains entry to host lung epithelial cells by the binding of the transmembrane spike (S) glycoprotein to ACE-2 (angiotensin-converting enzyme 2). The S1 subunit of the S protein binds to ACE-2 and mediates viral attachment. Proteolytic cleavage of the S protein at the S1/2 junction by the proteases, furin, and TMPRSS-2 (transmembrane protease serine 2), facilitates viral entry. SARS-CoV-2 can also directly invade endothelial expressed ACE-2. Infected cells undergo pyroptosis leading to the release of danger-associated molecular patterns (DAMPs) and triggering the release of proinflammatory cytokines and chemokines. The activated endothelium upregulates the expression of VWF (von Willebrand factor) and adhesion molecules including ICAM (intercellular adhesion molecule)-1, αvβ3, P-selectin and E-selectin leading to recruitment of platelets and leukocytes and complement activation. Neutrophils release neutrophil extracellular traps (NETS), causing direct activation of the contact pathway. Complement activation potentiates these mechanisms by increasing endothelial and monocyte tissue factor (TF), further platelet activation and amplifies endothelial inflammation, which increases production of proinflammatory cytokines from the endothelium including IL (interleukin)-1, IL-8, RANTES (regulated on activation, normal T-cell expressed and secreted), IL-6, and MCP (monocyte chemoattractant protein)-1. The hypoxic environment can induce HIFs (hypoxia-inducible factors) which upregulates endothelial TF expression. These mechanisms ultimately lead to the unchecked generation of thrombin, resulting in thrombus formation. The fibrin degradation product, D-dimer, which is a marker of coagulation activation, appears to be a strong prognostic marker associated with high mortality in patients with COVID-19.