Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is at present an emerging global public health crisis.Angiotensin converting enzyme 2 (ACE2) and trans-membrane protease serine 2 (TMPRSS2) are the two major host factors that contributeto the virulence of SARS-CoV-2 and pathogenesis of coronavirus disease-19 (COVID-19). Transmission of SARS-CoV-2 from animal tohuman is considered a rare event that necessarily requires strong evolutionary adaptations. Till date no other human cellular receptors areidentified beside ACE2 for SARS-CoV-2 entry inside the human cell. Proteolytic cleavage of viral spike (S)-protein and ACE2 byTMPRSS2 began the entire host–pathogen interaction initiated with the physical binding of ACE2 to S-protein. SARS-CoV-2 S-proteinbinds to ACE2 with much higher affinity and stability than that of SARS-CoVs. Molecular interactions between ACE2-S and TMPRSS2-Sare crucial and preciously mediated by specific residues. Structural stability, binding affinity and level of expression of these threeinteracting proteins are key susceptibility factors for COVID-19. Specific protein–protein interactions (PPI) are being identified thatexplains uniqueness of SARS-CoV-2 infection. Amino acid substitutions due to naturally occurring genetic polymorphisms potentially alterthese PPIs and poses further clinical heterogeneity of COVID-19. Repurposing of several phytochemicals and approved drugs againstACE2, TMPRSS2 and S-protein have been proposed that could inhibit PPI between them. We have also identified some novel leadphytochemicals present in Azadirachta indica and Aloe barbadensis which could be utilized for further in vitro and in vivo anti-COVID-19drug discovery. Uncovering details of ACE2-S and TMPRSS2-S interactions would further contribute to future research on COVID-19.

Clinical and public health research has revealed the co-occurrence of several neuropsychiatric diseases among patients with celiac disease (CD). The significant presence of CD-specific autoantibodies in patients with neuropsychiatric diseases and vice versa are often reported. To explain the genetic basis of such frequent disease co-occurrence and investigate the underlying common pathways/processes, we performed an extensive cross-disease association study followed by supporting in silico functional validation of the leads. Genomewide association study (GWAS) data for CD and eight commonly co-occurring neuropsychiatric diseases from Caucasian populations were analysed, and the shared loci were determined.We performed Immunochip-based fine mapping of these overlapping association signals in anindependent European CD data and tested their cross-ethnic transferability using CD association data from the genetically distinct north Indian population. This study identified 12 shared loci between the two diseases with genomewide significance (P ≤ 5e-8). Of these five loci, namely NFIA, KIA1109, NOTCH4-TSBP1-PBX2, HLA-DQA1 and CSK replicated in an independent Dutch cohort representing European ancestry. Three of these loci, namely NFIA, NOTCH4-TSBP1-PBX2 and HLA-DQA1 that are common between CD, anxiety, migraine and schizophrenia respectively withstood locus transferability test in north Indians. Tissue-specific eQTL analysis of SNPs from transferable loci revealedexpression QTL effects in brain tissue besides the small intestine and whole blood. Pathway analysis and evidence of epigenetic regulation highlighted the potential contribution of these SNPs to disease pathology. The replicable and transferable association of genetic variants from MHC locus and their functional implications suggest the process of antigen presentation and adaptive/innate immune response regulated by non-HLA genes in the locus may dominate the shared pathogenesis of CD and neuropsychiatric diseases. Functional validation of the shared candidate genes is warranted to unravel the molecular mechanism for the co-occurrence of CD and specific neuropsychiatric diseases.