Pathogenesis 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. 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. Since ACE2 is extensively expressed in the nasal mucosa, bronchus, lung, heart, and kidney, etc., many human organs are vulnerable to SARS-CoV-2. 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. 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. 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. 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. 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.

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. 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. Additionally, only a few interstitial mononuclear inflammatory infiltrates were found in the heart tissue, meaning that this virus may not directly induce heart impairment. 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. 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. Intriguingly, a recent research compared the transcriptional responses of SARS-CoV-2 with other respiratory viruses to identify the transcriptional features that might form the biological basis of COVID-19. Their work demonstrated that the overall transcriptional induction of SARS-CoV-2 is abnormal. Despite viral replication, the host's response to SARS-CoV-2 failed to initiate powerful responses of type I and III interferons (IFN-I and -III), and at the same time induced high levels of chemokines required to recruit effector cells. In other words, this unique inflammatory response was defined by low levels of IFN-I and -III juxtaposed to elevated chemokines and high expression of IL-6. The reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production may be the defining and driving features of COVID-19. Moreover, because the weakened immune response will further enable sustained viral replication, this critical finding may explain why severe cases of COVID-19 are more frequently observed in patients with comorbidities.

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