The infection mechanisms of SARS-CoV-2
A nucleocapsid protein is structured by a phosphorylated capsid protein and the single strand of RNA. This structure allows membrane protein interact with nucleocapsid protein when the virion particles are pachaged, and supports the viral genome transcription. The nucleocapsid is hidden within the phospholipid bilayers and coated by spike glycoprotein trimer (S) and probably the hemagglutinin-esterase (HE) protein. Spike protein on the lipid envelope gives SARS-CoV-2 crown-like spikes, and thus form a classic coronavirus structure. Among the spikes site the membrane (M) protein, designers of the viral envelope’s shape by interacting with the nucleocapsid and by specific packaging of the viral genome into the virion, and the envelope (E) protein, viroporins that modify the host cell membranes and facilitates viruses release from the infected cells. The spike (S) protein of coronaviruses, binding to a cellular receptor through the receptor-binding domain (RBD) in the S1 subunit and followed by the fusion of the S2 subunit to the cell membrane, can facilitate viral entry into target cells. And S proteins are activated by priming cleavage between S1 and S2 and activating cleavage on S2’ site by different host cell proteases, including furin, transmembrane protease serine protease-2 (TMPRSS-2), TMPRSS-4, cathepsins, trypsin, or human airway trypsin-like protease (Coutard et al., 2020). Replication of coronaviruses starts from attachment and entry (Figure 1). When the S protein interacts with its specific receptor, the virus attaches to the host cell.and then enters host cell cytosol via cleavage of S protein by a protease enzyme, bring the outcome that the viral and cellular membranes blend together. Afterward, the replicase gene is interpreted from the virion genomic RNA and then the viral replicase-transcriptase complexes are translated and assembled. The virus then synthesizes RNA via its RNA-dependent RNA polymerase. The replication and RNA synthesis bring up the encapsidation that leads to the formation of the mature virus. Following assembly, vesicles carry virions to the cell surfaceand release them through exocytosis. Recently, a study reported that the non-structural protein 16 (nsp16) of SARS-CoV-2 mimics cellular mRNAs by methylating the 5’-end of virally encoded mRNAs to avoid host innate immunity(Viswanathan et al., 2020).
Based on the sequence similarity between SARS-CoV and SARS-CoV-2, most amino acid residues essential for angiotensin-converting enzyme 2 (ACE2) binding by SARS-CoV were conserved in SARS-CoV-2. Most of these residues did not exist in the S proteins of several SARS-CoV-related viruses from bats, which had been found not to use ACE2 for entry (Ge et al., 2013). A mouse model of SARS-CoV infection revealed that the infection degree of the disease increases with the overexpression of human ACE2, which indicates that ACE2 is critical for viral entry into cells (X. H. Yang et al., 2007). Studies show that ACE2 proteins expressed on human HeLa cells, Chinese horseshoe bats, civets, and pigs, allowed host cell entry and subsequent viral replication (P. Zhou et al., 2020). SARS-CoV-2 uses the SARS-CoV receptor ACE2 entry into host cells. The affinity between ACE2 and the S protein of SARS-CoV-2 is much higher than that of the S protein of SARS-CoV. The human-to-human transmission of SARS-CoV-2 seems easier. Furthermore, serine protease TMPRSS2 prepares the S protein for SARS-CoV-2 (Hoffmann et al., 2020).
It is well established that the ACE2 receptor has been found on many cells’ surface (Lukassen et al., 2020). The level of ACE2 expression has an impact on infection in different tissues. Human ACE2 is primarily expressed on type II and type I alveolar epithelial cells, suggesting that these tissues are susceptible to the virus. The risk of infection is higher than in tissues with low expression levels of ACE2. Pneumonia-associated symptoms of infected patients indicate that SARS-CoV-2 primarily infects the respiratory tract, which becomes the transmission route of the virus (Chaolin Huang et al., 2020). A previous study revealed that different tissues expressed different levels of ACE2, and the data indicated that SARS-CoV-2 may infect other human tissues (i.e., duodenum, small intestine, and heart) besides the lungs. For instance, stool from patients with SARS-CoV-2 was in favour for SARS-CoV-2, which gives a hint that the gastrointestinal tract may be infected by the virus (Smith & Turner, 2004), which is in accordance with the high-level ACE2 expression in the gastrointestinal tract (i.e. stomach, duodenum, and rectal epithelial cells) (Bao et al., 2020). Furthermore, a previous study showed that ACE2 can protect from acute lung failure except for facilitating viral entry, which suggests that the ACE2-Ang (1–7)-Mas axis can be carefully manipulated to mitigate SARS-induced tissue injuries(Imai et al., 2005; Kuba et al., 2005). In this way, it offers a potential target for therapeutic intervention.