Structure, function and variants analysis of the androgen-regulated TMPRSS2 , a drug target candidate for COVID-19 infection

  1. Alessia David
  2. Tarun Khanna
  3. Melina Beykou
  4. Gordon Hanna
  5. Michael J E Sternberg

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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.

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    In addition, we used the SIFT (Vaser et al., 2016) and Polyphen2 (Adzhubei et al., 2010) variant predictors, which mainly use evolutionary conservation to assess a variant’s effect.
    SIFT
    suggested: (SIFT, RRID:SCR_012813)
    Polyphen2
    suggested: None
    CONDEL (González-Pérez and López-Bigas, 2011) which reports a weighted average of the scores from fatHMM and MutationAssessor, and ii.
    MutationAssessor
    suggested: (MutationAssessor, RRID:SCR_005762)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

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    IdentifierStatusTitle
    NCT04321096Active, not recruitingThe Impact of Camostat Mesilate on COVID-19 Infection

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    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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