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AbstractSARS-CoV-2, a highly transmittable pathogen has infected over 3.8 million people around the globe. The spike glycoprotein of SARS-CoV-2 engages host ACE2 for adhesion, TMPRSS2 for activation and entry. With the aid of whole-exome sequencing, we report a variant rs12329760 in TMPRSS2 gene and its mutant V160M, which might impede viral entry. Furthermore, we identified TMPRSS2 cleavage sites in S2 domain of spike glycoprotein and report the structure of TMPRSS2 in complex with spike glycoprotein. We also report the structures of protease inhibitors in complex with TMPRSS2, which could hamper the interaction with spike protein. These findings advance our understanding on the role of TMPRSS2 and in the development of potential therapeutics.

Introduction Human leukocyte antigen (HLA) variability has been demonstrated to be associated with susceptibility/severity of COVID‐19. High‐resolution HLA genotyping to identify alleles associated with severe COVID‐19 in an Indian cohort was performed. Methods Quantitative reverse‐transcription polymerase chain reaction‐confirmed SARS‐CoV‐2‐positive patients with mild/moderate/severe disease ( n = 54) and asymptomatic ( n = 42) were recruited and genotyped for 11‐HLA loci on MiSeq using NGSgo®‐MX11‐3 and analyzed (NGSengine; GenDx). Results A significant difference in alleles between the groups was identified for HLA‐C*04:01:01:01, HLA‐DRB5*01:01:01:02, HLA‐DQA1*03:01:01:01, HLA‐DPB1*04:01:01:41, and HLA‐DPA1*01:03:01:02. Alleles namely, HLA‐C*04:01:01:01 (OR: 5.71; 95% CI: 1.2–27.14; p = .02), HLA‐DRB5*01:01:01:02 (OR: 2.94; 95% CI: 1.1–7.84; p = .03), DQA1*03:01:01:01 (OR: 22.47; 95% CI: 1.28–393.5; p = .03), HLA‐DPB1*04:01:01:41 (OR: 9.44; 95% CI: 0.5–175.81; p = .13), and HLA‐DPA1*01:03:01:02 (OR: 8.27; 95% CI: 2.26–30.21; p = .001) were associated with severe COVID‐19. Conclusion Genotyping for these alleles will enable identification of individuals at risk of severe disease and stratification for preferential vaccination.