Figure 4. COVID-19 diagnostic test by RT-PCR.
4.2Pathogenesis
of SARS-CoV-2
With regard to the transmission of SARS-CoV-2, primary viral replication
is assumed to occur in the mucosal epithelium of the upper respiratory
tract and further multiplicated in the lower respiratory tract and
gastrointestinal mucosa, inducing a mild viremia (Xiao et al., 2020). At
this point, very few infections are under control and remain
asymptomatic. Some patients may also suffer non-respiratory symptoms
(i.e., acute liver and heart injury, renal failure, diarrhea),
suggesting multiple organ involvement (Huang et al., 2020; D. Wang et
al., 2020). Since ACE2 is extensively expressed in the nasal mucosa,
bronchus, lung, heart, and kidney, etc., many human organs are
vulnerable to SARS-CoV-2 (Zou et al., 2020). Specifically, the S protein
plays a critical role in determining the cell tropism and hence
interspecies transmission of SARS-CoV-2 since it hitches the virus to a
cellular receptor and subsequently prompts virus entry via membrane
fusion (Wrapp et al., 2020). After binding to the receptor, the spike
protein can catalyze the viral fusion process, allowing the viral genome
to enter the cytoplasm. A prerequisite for this procedure is the
division of S to subunits, a process known as priming (Figure 3). The
work of Hoffmann et al. unraveled that SARS-CoV-2 utilizes the ACE2
receptor for entry and the serine protease TMPRSS2 for S protein priming
(Hoffmann et al., 2020). Hence, TMPRSS2 inhibitors approved for clinical
use may block the entrance and may give rise to an underlying treatment
option. Notably, the ability that S can readily obtain new protease
cleavage sites and the fact that miscellaneous proteases can perform the
same task suggests that this virus can easily adapt to the proliferation
in several cell types (Walls et al., 2020). Further, a panel of murine
monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against
SARS-CoV-S1/receptor-binding domain (RBD) had been reported to be unable
to interplay with S protein, implicating conspicuous discrepancies in
antigenicity between SARS-CoV-2 and SARS-CoV (Wang et al., 2020c).
According to the pathological findings, the first report on the
pathological results of severe COVID-19 revealed that diffuse alveolar
injury on both sides of the lung was accompanied by cellular fibromyxoid
exudates (Xu et al., 2020). The right lung displayed significant lung
cell shedding and hyaline membrane formation, suggesting ARDS. Moreover,
the left lung tissue showed pulmonary edema and hyaline membrane
formation, implying early ARDS. Interstitial mononuclear inflammatory
infiltrates, dominated by lymphocytes, were found in both lungs. Another
study reported that acute kidney injury and proteinuria might also occur
during the progression of COVID-19 disease. ACE2 was seen to be
upregulated in COVID-19 patients, and immunostaining with the SARS-CoV
nucleoprotein antibody was positive in tubules (Su et al., 2020).
Additionally, only a few interstitial mononuclear inflammatory
infiltrates were found in the heart tissue, meaning that this virus may
not directly induce heart impairment (Xu et al., 2020). Aside from the
acute respiratory distress syndrome, exuberant inflammatory responses
during the infection process were also observed in clinical, giving rise
to unrestrained pulmonary inflammation. Of note, the virus-induced ACE2
downregulation, rapid virus replication and cell damage, and
antibody-dependent enhancement may lead to aggressive inflammation
aroused by SARS-CoV-2 (Fu et al., 2020). The initial stage of rapid
viral replication would induce a large number of epithelial and
endothelial cell death, thereby facilitating the generation of raging
pro-inflammatory cytokines and chemokines (Figure 5) (Yang, 2020). In
addition to the cytokine storm, several experimentations had unraveled
that lymphopenia is a customary characteristic of COVID-19, which may
also accounts for severity and mortality (Huang et al., 2020; Zhu et
al., 2020).