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.