Assessment of risk conferred by coding and regulatory variations of TMPRSS2 and CD26 in susceptibility to SARS-CoV-2 infection in human

Abstract

At present, more than 200 countries and territories are directly affected by the coronavirus disease-19 (COVID-19) pandemic. Incidence and case fatality rate are significantly higher among elderly individuals (age [ 60 years), type 2 diabetes and hypertension patients. Cellular receptor ACE2, serine protease TMPRSS2 and exopeptidase CD26 (also known as DPP4) are the three membrane bound proteins potentially implicated in SARS-CoV-2 infection. We hypothesised that common variants from TMPRSS2 and CD26 may play critical role in infection susceptibility of predisposed population or group of individuals. Coding (missense) and regulatory variants from TMPRSS2 and CD26 were studied across 26 global populations. Two missense and five regulatory SNPs were identified to have differential allelic frequency. Significant linkage disequilibrium (LD) signature was observed in different populations. Modelled protein-protein interaction (PPI) predicted strong molecular interaction between these two receptors and SARS-CoV-2 spike protein (S1 domain). However, two missense SNPs, rs12329760 (TMPRSS2) and rs1129599 (CD26), were not found to be involved physically in the said interaction. Four regulatory variants (rs112657409, rs11910678, rs77675406 and rs713400) from TMPRSS2 were found to influence the expression of TMPRSS2 and pathologically relevant MX1. rs13015258 a 5 0 UTR variant from CD26 have significant role in regulation of expression of key regulatory genes that could be involved in SARS-CoV-2 internalization. Overexpression of CD26 through epigenetic modification at rs13015258-C allele was found critical and could explain the higher SARS-CoV-2 infected fatality rate among type 2 diabetes.

Contributions of human ACE2 and TMPRSS2 in determining host–pathogen interaction of COVID-19

“… Amino acid residues of TMPRSS2 Amino acid residues of S protein Publications Gly190, Asn192, Pro191, Phe195, Tyr189, Ser234, Lys399, Asp396, Asn395, Thr324, Ala280, Cys278, Arg277, Phe251, Ile279, Phe394, Tyr232, Asn284, Val283, Gln290, Leu285, Pro325, Asn488, Ser287, Ser288, Ile489, Asn286, Thr393 S1 domain: Trp64, Tyr266, Ala264, Thr95, Ala263, Val213, Ala262, Lys187, Arg214, Arg237, Gly261, Asn211, Asp215, His66, Leu242, Asp80, Phe79, Val183, Pro82, His245, Leu244, Leu84, Arg246, Phe65, Pro85, Tyr269, Asn61, Tyr28, VAl62, Thr63, Asn137, Asp614 Arg667, Arg797 S1-S2 junction: Leu611 , Asp614 , Gln675 , Ala706 S2 domain: Ala831 , Asp839 , Ala845 , Ala846 , Ala852 , Ala930 , Asp936 , Ser939 , Ser940 , Thr941 , Ser943 , Asp1163 Senapati et al . ( 2020 ) Hoffmann et al . ( 2020 ) Bhattacharyya et al .…”

“…Common TMPRSS2 missense variation rs12329760 was found not involving in direct interaction with S-protein, but potentially influence the structural confirmation (Senapati et al . 2020 ). Four common regulatory SNPs present at the 3’UTR (rs112657409, rs11910678, rs77675406) and 5’ flanking (rs713400) of TMPRSS2 were found to significantly influence the expression (eQTL P ≤ 2.00E-05) of MX1 and TMPRSS2 .…”

Identification of FDA approved drugs and nucleoside analogues as potential SARS-CoV-2 A1pp domain inhibitor: An in silico study

“…For molecular docking studies, the receptor (PDB ID: 6W02 ) and the ligands were loaded onto Auto Dock Tools 1.5.6 (ADT) [ 14 , 15 ]. Gestgeiger partial charges were assigned after merging non-polar hydrogen bonds and torsions to the ligands.…”

Could SARS-CoV-2-induced lung injury be attenuated by vitamin D?

“…As the host cell receptor of SARS-CoV-2, ACE2 exists as a dimer that includes the N-terminal peptidase domain (PD) and the C-terminal collectrin-like domain (CLD) ( Zhang et al, 2020 ). The PD of ACE2 recognizes the spike protein of SARS-CoV-2, and the CLD of ACE2 is cleaved by proteases such as transmembrane serine protease 2 (TMPRSS2), thus promoting SARS-CoV-2 spike protein-mediated entry into cells ( Senapati et al, 2020 ). Specifically, decreased expression of proteins such as ACE2 and TMPRSS2 in the airway epithelium in children may reduce viral entry, which might be the reason why SARS-CoV-2 leads to decreased lung injury in children compared with adults ( Lingappan et al, 2020 ).…”