COVID-19 susceptibility: potential of ACE2 polymorphisms

Abstract

Background: Angiotensin-converting enzyme 2 (ACE2) is a metallopeptidase that primarily functions as a negative regulator of renin angiotensin system (RAS) by converting angiotensin II (Ang II) to angiotensin 1-7. Contrary to this, another RAS component, angiotensin-converting enzyme (ACE) catalyzes synthesis of Ang II from angiotensin I (Ang I) that functions as active compound in blood pressure regulation. This indicates importance of ACE/ACE2 level in regulating blood pressure by targeting Ang II. An outbreak of severe acute respiratory syndrome (SARS) highlighted the additional role of ACE2 as a receptor for SARS coronavirus (SARS-CoV) infection.

Main body of the abstract: ACE2 is a functional receptor for SARS-CoV and SARS-CoV-2. Activation of spike (S)-protein by either type II transmembrane serine proteases (TTSPs) or cathepsin-mediated cleavage initiates receptor binding and viral entry. In addition to TTSPs, ACE2 can also be trimmed by ADAM 17 (a disintegrin and metalloproteinase 17) that competes for the same receptor. Cleavage by TTSPs activates ACE2 receptor for binding, whereas ADAM17 releases extracellular fragment called soluble ACE2 (sACE2). Structural studies of both ACE2 and S-protein have found critical sites involved in binding mechanism. In addition to studies on structural motifs, few single-nucleotide polymorphism (SNPs) studies have been done to find an association between genetic variants and SARS susceptibility. Though no association was found in those reports, but seeing the non-reproducibility of SNP studies among different ethnic groups, screening of ACE2 SNPs in individual population can be undertaken.

Short conclusion: Thus, screening for novel SNPs focussing on recently identified critical regions of ACE2 can be targeted to monitor susceptibility towards coronavirus disease 2019 (COVID-19).

Keywords: ACE2; COVID-19; Coronavirus; SARS-CoV-2; Severe acute respiratory syndrome (SARS); Single-nucleotide polymorphism (SNP).

Fig. 1

Possible relation between renin-angiotensin system inhibition and COVID-19 [adapted from 19]. Competing hypothetical mechanisms by which use of ACEIs and ARBs might be harmful or protective in COVID-19. Hypothesis 1: SARS-CoV-2 enters cell by binding to ACE2. Use of ACEIs and ARBs could increase ACE2 abundance and enhance viral entry. Hypothesis 2: Ang II causes lung injury through inflammation and fibrosis upon activation of AT1R. Reduced production of Ang II by ACEIs or blockade of Ang II-AT1R interaction by ARBs increases generation of Ang (1-7) by ACE2 and activates Mas receptor (MasR) causing reduction in inflammation and fibrosis and thereby attenuating lung injury

Fig. 2

Action of host cell proteases on ACE2 receptor [adapted from 35]. Cleavage of ACE2 by ADAM17 causes its shedding. Interaction of sACE2 with S-Protein of SARS-CoV prevents binding of virus particles to target cells. Co-expression of TMPRSS2 with ACE2 on target cell surface involves binding of SARS-CoV (S-protein) to ACE2- and TMPRSS2-mediated processing allows fusion and uptake of virus particles

Fig. 3

Possible role of novel ACE2 SNPs in susceptibility towards SARS-CoV-2. Presence of SNPs within coding region can result in alteration of amino acid sequence. This change in amino acid sequence at site of interaction can affect the binding capacity of ACE2 receptor with S-Protein of SARS-CoV-2. Novel SNPs within promoter or 3′-UTR can cause downregulation of ACE2 gene resulting in lower levels of ACE2 receptor at cell surface for interaction with virus particles