Structure, function and variants analysis of the androgen-regulatedTMPRSS2, a drug target candidate for COVID-19 infection

Abstract

SARS-CoV-2 is a novel virus causing mainly respiratory, but also gastrointestinal symptoms. Elucidating the molecular processes underlying SARS-CoV-2 infection, and how the genetic background of an individual is responsible for the variability in clinical presentation and severity of COVID-19 is essential in understanding this disease.Cell infection by the SARS-CoV-2 virus requires binding of its Spike (S) protein to the ACE2 cell surface protein and priming of the S by the serine protease TMPRSS2. One may expect that genetic variants leading to a defective TMPRSS2 protein can affect SARS-CoV-2 ability to infect cells. We used a range of bioinformatics methods to estimate the prevalence and pathogenicity of TMPRSS2 genetic variants in the human population, and assess whether TMPRSS2 and ACE2 are co-expressed in the intestine, similarly to what is observed in lungs.We generated a 3D structural model of the TMPRSS2 extracellular domain using the prediction server Phyre and studied 378 naturally-occurring TMPRSS2 variants reported in the GnomAD database. One common variant, p.V160M (rs12329760), is predicted damaging by both SIFT and PolyPhen2 and has a MAF of 0.25. Valine 160 is a highly conserved residue within the SRCS domain. The SRCS is found in proteins involved in host defence, such as CD5 and CD6, but its role in TMPRSS2 remains unknown. 84 rare variants (53 missense and 31 leading to a prematurely truncated protein, cumulative minor allele frequency (MAF) 7.34×10−4) cause structural destabilization and possibly protein misfolding, and are also predicted damaging by SIFT and PolyPhen2 prediction tools. Moreover, we extracted gene expression data from the human protein atlas and showed that both ACE2 and TMPRSS2 are expressed in the small intestine, duodenum and colon, as well as the kidneys and gallbladder.The implications of our study are that: i. TMPRSS2 variants, in particular p.V160M with a MAF of 0.25, should be investigated as a possible marker of disease severity and prognosis in COVID-19 and ii. in vitro validation of the co-expression of TMPRSS2 and ACE2 in gastro-intestinal is warranted.

Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease

“…These observations suggest that inhibition of TMPRSS2 might be protective against COVID-19. Consistent with this hypothesis, we found that the missense variant that was associated with protection from COVID-19 (rs12329760, p.V160M; Supplementary Table 11 ) is predicted to be deleterious by SIFT [50], PolyPhen2-HVAR and PolyPhen2-HDIV [51] and is also predicted to decrease protein stability in structural models [52, 53]. These results provide human genetic support for loss of TMPRSS2 in SARS-CoV-2 infection and suggest that TMPRSS2 blockade might protect against worse COVID-19 outcomes.…”

Impact of natural selection on global patterns of genetic variation, and association with clinical phenotypes, at genes involved in SARS-CoV-2 infection

“…In total, 13 non-synonymous variants located on different structural domains of TMPRSS2 were fixed in human populations. Among them, E441Q and T515M are located in the Peptidase S1 domain that plays an important role in acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) infection 78 and six (A3P, N10S, T46P, A70V, R103C, and M104T) are at the cytoplasmic amino terminal domains of TMPRSS2 which plays an important role in signal transduction. These variants at TMPRSS2 could be potential candidates for future studies to investigate their functional impact on susceptibility to pathogens in humans compared to non-human primates.…”

Impact of natural selection on global patterns of genetic variation, and association with clinical phenotypes, at genes involved in SARS-CoV-2 infection.

“…In total, 13 non-synonymous variants located on different structural domains of TMPRSS2 were xed in human populations. Among them, E441Q and T515M are located in the Peptidase S1 domain that plays an important role in acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) infection 63 and six (A3P, N10S, T46P, A70V, R103C, and M104T) are at the cytoplasmic amino terminal domains of TMPRSS2 which plays an important role in signal transduction. These variants at TMPRSS2 could be potential candidates for future studies to investigate their functional impact on susceptibility to pathogens in humans compared to non-human primates.…”