Understanding on the possible routes for SARS CoV-2 invasion via ACE2 in the host linked with multiple organs damage

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accountable for causing the coronavirus diseases 2019 (COVID-19), is already declared as a pandemic disease globally. Like previously reported SARS-CoV strain, the novel SARS-CoV-2 also initiates the viral pathogenesis via docking viral spike-protein with the membranal angiotensin-converting enzyme 2 (ACE2) - a receptor on variety of cells in the human body. Therefore, COVID-19 is broadly characterized as a disease that targets multiple organs, particularly causing acute complications via organ-specific pathogenesis accompanied by destruction of ACE2⁺ cells, including alveolus, cardiac microvasculature, endothelium, and glomerulus. Under such circumstances, the high expression of ACE2 in predisposing individuals associated with anomalous production of the renin-angiotensin system (RAS) may promote enhanced viral load in COVID-19, which comparatively triggers excessive apoptosis. Furthermore, multi-organ injuries were found linked to altered ACE2 expression and inequality between the ACE2/angiotensin-(1-7)/mitochondrial Ang system (MAS) and renin-angiotensin-system (RAS) in COVID-19 patients. However, the exact pathogenesis of multi-organ damage in COVID-19 is still obscure, but several perspectives have been postulated, involving altered ACE2 expression linked with direct/indirect damages by the virus-induced immune responses, such as cytokinin storm. Thus, insights into the invasion of a virus with respect to ACE2 expression site can be helpful to simulate or understand the possible complications in the targeted organ during viral infection. Hence, this review summarizes the multiple organs invasion by SARS CoV-2 linked with ACE2 expression and their consequences, which can be helpful in the management of the COVID-19 pathogenesis under life-threatening conditions.

Keywords: Angiotensin-(1-7); COVID-19; Extrapulmonary manifestation; Multiorgan damage; Pneumonia; SARS-CoV-2.

Graphical abstract

Fig. 1

Structural interactions between the glycosylated S-protein of SARS-CoV-2 with the membranal TMPRSS2 and ACE2 receptors on the target cell. TMPRSS2 instigate the activation of S-protein to expose receptor-binding domain (RBD) for the attachment with its functional receptor ACE2 for binding and fusion with the host cell.

Fig. 2

A dubious position of interferon (IFN) in SARS-CoV-2 pathogenesis by augmenting the expression of membranal ACE2 receptor. The invasion of SARS-CoV-2 promotes IFN expression, which further activates the high expression of AEC2 and canonical ISGs genes while ACE2 upregulation may promotes acute infection by SARS-CoV-2. Moreover, ACE2 assists to shield the host against acute organ or tissue damage via incapacitating the ang-II molecules. Meanwhile, generated ISGs signals may possibly trigger the broad immune reactions, which further promote the inhibition of infection caused by SARS-CoV-2 and acute lung injuries via augmenting the inflammatory responses.

Fig. 3

Schematic of SARS-CoV-2 infection in the lungs followed by proliferation to other vital organs containing special cells with elevated expression of ACE2 receptor. At first, viral particles are assumed to invade the lungs and attack the cells expressing ACE2 receptors after activation of S-protein by membranal TMPRSS2 and other transmembrane proteinases like disintegrin metallopeptidase domain 17 (ADAM17) of the host, exploited by the virus to enter in the cells. In response to the viral entrance, virus-invaded cells along with the inflammatory cells generate PICs and chemokines that facilitate the inflammatory and immunological responses to halt the viral propagation. The cell-free viruses and the viruses phagocytosed by the macrophages situated in the blood are probably transported to other organs of the infected host body and characteristically distress the cells with elevated expression of ACE2 at resident sites (Ni et al., 2020).