S Protein, ACE2 and Host Cell Proteases in SARS-CoV-2 Cell Entry and Infectivity; Is Soluble ACE2 a Two Blade Sword? A Narrative Review

Abstract

Since the spread of the deadly virus SARS-CoV-2 in late 2019, researchers have restlessly sought to unravel how the virus enters the host cells. Some proteins on each side of the interaction between the virus and the host cells are involved as the major contributors to this process: (1) the nano-machine spike protein on behalf of the virus, (2) angiotensin converting enzyme II, the mono-carboxypeptidase and the key component of renin angiotensin system on behalf of the host cell, (3) some host proteases and proteins exploited by SARS-CoV-2. In this review, the complex process of SARS-CoV-2 entrance into the host cells with the contribution of the involved host proteins as well as the sequential conformational changes in the spike protein tending to increase the probability of complexification of the latter with angiotensin converting enzyme II, the receptor of the virus on the host cells, are discussed. Moreover, the release of the catalytic ectodomain of angiotensin converting enzyme II as its soluble form in the extracellular space and its positive or negative impact on the infectivity of the virus are considered.

Variants of SARS-CoV-2: Influences on the Vaccines’ Effectiveness and Possible Strategies to Overcome Their Consequences

“…Hence, the S Protein is the main target of SARS-CoV-2 vaccines, and it exists as a homotrimer in the viral envelope with its membrane-distal S1 and S2 subunits (which are membrane-proximal). S1′s receptor-binding domain modulates receptor recognition [ 66 , 67 , 89 ]. It is imperative to mention here that the N-terminal domain (NTD) of the subunit S1 could also serve as a receptor-interacting domain, as in the case of the mouse hepatitis virus [ 90 , 91 , 92 ].…”

Role of the RAAS in mediating the pathophysiology of COVID-19

“…The rhsACE2 is believed to inhibit mACE2 shedding by blocking binding sites in the RBD of the virus, potentially restoring the local Ang II/Ang 1–7 ratio in favor of the latter. The ACE2/Ang 1–7/Mas receptor (MasR) axis has anti-inflammatory effects, which may reduce the release of damaging cytokines [ 37 ]. Some experts have explored strategies such as the production of sACE2-IgG conjugates to enhance the activity and half-life of rhsACE2 against SARS-CoV-2 infection [ 38 ].…”

“…COVID-19 infection also upregulates ADAM17 expression at both protein and transcript levels [ 42 ]. sACE2 levels also increase in pathologies associated with higher AT1R stimulation, such as myocardial infarction, heart failure (HF), metabolic syndrome, and diabetes [ 37 ]. Interestingly, when analyzing subjects diagnosed with heart failure with reduced ejection fraction (HFrEF) or with mid-range ejection fraction (HFmrEF), Conti et al described a significant positive correlation between Sirtuin 1 (Sirt1) activity in peripheral blood mononuclear cells and both circulating ACE2 concentrations and the ejection fraction (EF).…”

Analyzing the role of ACE2, AR, MX1 and TMPRSS2 genetic markers for COVID-19 severity

“…Moreover, there are studies suggesting that TMPRSS2 rs75603675 genotype combined with dyslipidemia and gender, are main predictors of disease severity [ 3 ]. This gene acts jointly with ACE2 , and both have been included as the two major host factors contributing to SARS-CoV-2 virulence and pathogenesis [ 4 ]. There are a growing number of studies showing the abnormal predominance of pro-inflammatory ACE/Ang II/AT1R/Nox over anti-inflammatory ACE2/Angiotensin/MasR pathways as the probable cause of chaotic inflammatory responses in COVID-19 [ 4 ].…”

“…This gene acts jointly with ACE2 , and both have been included as the two major host factors contributing to SARS-CoV-2 virulence and pathogenesis [ 4 ]. There are a growing number of studies showing the abnormal predominance of pro-inflammatory ACE/Ang II/AT1R/Nox over anti-inflammatory ACE2/Angiotensin/MasR pathways as the probable cause of chaotic inflammatory responses in COVID-19 [ 4 ]. The human myxovirus resistance genes ( MX ) encode GTPases that are part of the antiviral response induced by type I/III IFNs.…”