3.10. Pathogenic Mechanisms
Many studies have been performed to study the pathogenesis of SARS-CoV [94,95,96]. The spike (S) protein and N protein confer stability to the viral particle [97]. The N protein is a structural protein involved in virion assembly, and plays a pivotal role in virus transcription and assembly efficiency [97]. S protein can bind to the cellular receptors of sensitive cells and mediate infection of their target cells, after which it begins to replicate in the cytoplasm [98]. SARS-CoV mainly targets the lungs, immune organs, and small systemic blood vessels and causes systemic vasculitis and decrease of immune function [99]. More seriously, the infection leads to extensive pulmonary consolidation, diffuse alveolar damage, and the formation of a transparent membrane, finally deteriorating to respiratory distress [100].
CoV can enter host cells through the interaction between CoV S protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which is isolated from SARS-CoV–permissive Vero-E6 cells. The receptor-binding motif (RBM) of S protein can directly contact ACE2 [47,101,102]. AEC2 have been identified to be key binding residues and functional receptor for SARS-CoV, and it can also protect alveolar cells [103]. The binding of spike protein to ACE2 and the subsequent downregulation of this receptor contribute to severe alveolar injury during SARS [49]. The downregulation of ACE2 results in the excessive production of angiotensin II by the related enzyme ACE, and the stimulation of type 1A angiotensin II receptor (AGTR1A) can lead to the increase of pulmonary vascular permeability, which potentially explains the increased lung pathology when the expression of ACE2 is decreased [104]. ACE2-transfected T cells form multinucleated syncytia with cells expressing S protein. The virus was shown to replicate effectively in ACE2-transfected, but not in mock-transfected T cells. Antibodies targeting ACE2 can block viral replication in Vero-E6 cells [105].
Recently, Ji et al. demonstrated that the receptor binding domain of SARS-CoV-2 was capable of binding ACE2 in the context of the SARS-CoV spike protein [51]. Among SRAS-CoV spike protein’s fourteen residues predicted to interact directly with human ACE2 as the receptor for SARS-CoV, eight amino acids are well conserved in homology SARS-CoV-2 spike protein [26,102]. At the same time, Wan et al. showed that SARS-CoV-2 uses ACE2 receptors to infect humans, bats, civets, monkeys, and swine, but not mice [106]. Compared to previously reported SARS-CoV strains, SARS-CoV-2 uses ACE2 receptors more efficiently than human SARS-CoV (year 2003), but less efficiently than human SARS-CoV (year 2002) [106]. The mutation of proteins determines two important characteristics of the SARS-CoV-2: A higher ability to infect and enhanced pathogenicity than the bat-like SARS-CoV, but a lower pathogenicity than SARS-CoV [43].