Browsing by Author "Bhagavatula, Sandilya"

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    Contributions of human ACE2 and TMPRSS2 in determining host�pathogen interaction of COVID-19
    (Springer, 2021-02-25T00:00:00) Senapati, Sabyasachi; Banerjee, Pratibha; Bhagavatula, Sandilya; Kushwaha, Prem Prakash; Kumar, Shashank
    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 contribute to the virulence of SARS-CoV-2 and pathogenesis of coronavirus disease-19 (COVID-19). Transmission of SARS-CoV-2 from animal to human is considered a rare event that necessarily requires strong evolutionary adaptations. Till date no other human cellular receptors are identified beside ACE2 for SARS-CoV-2 entry inside the human cell. Proteolytic cleavage of viral spike (S)-protein and ACE2 by TMPRSS2 began the entire host�pathogen interaction initiated with the physical binding of ACE2 to S-protein. SARS-CoV-2 S-protein binds to ACE2 with much higher affinity and stability than that of SARS-CoVs. Molecular interactions between ACE2-S and TMPRSS2-S are crucial and preciously mediated by specific residues. Structural stability, binding affinity and level of expression of these three interacting proteins are key susceptibility factors for COVID-19. Specific protein�protein interactions (PPI) are being identified that explains uniqueness of SARS-CoV-2 infection. Amino acid substitutions due to naturally occurring genetic polymorphisms potentially alter these PPIs and poses further clinical heterogeneity of COVID-19. Repurposing of several phytochemicals and approved drugs against ACE2, TMPRSS2 and S-protein have been proposed that could inhibit PPI between them. We have also identified some novel lead phytochemicals present in Azadirachta indica and Aloe barbadensis which could be utilized for further in vitro and in vivo anti-COVID-19 drug discovery. Uncovering details of ACE2-S and TMPRSS2-S interactions would further contribute to future research on COVID-19. � 2021, Indian Academy of Sciences.
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    Multiple allelic associations from genes involved in energy metabolism were identified in celiac disease
    (Springer, 2021-06-23T00:00:00) Bhagavatula, Sandilya; Banerjee, Pratibha; Sood, Ajit; Midha, Vandana; Thelma, B.K.; Senapati, Sabyasachi
    Energy metabolism is a critical factor that influences disease pathogenesis. Recent high-throughput genomic studies have enabled us to look into disease biology with greater details. Celiac disease (CD) is an inflammatory autoimmune disease where ~60 non-HLA genes were identified which in conjunction with HLA genes explain ~55% of the disease heritability. In this study we aimed to identify susceptibility energy metabolism genes and investigate their role in CD. We re-analysed published Immunochip genotyping data, which were originally analysed for CD association studies in north Indian and Dutch population. 269 energy metabolism genes were tested. Meta-analysis was done for the identified SNPs. To validate the functional implications of identified markers and/or genes, in silico functional annotation was performed. Six SNPs were identified in north Indians, of which three markers from two loci were replicated in Dutch. rs2071592 (PMeta=5.01e?75) and rs2251824 (PMeta=1.87e?14) from ATP6V1G2-NFKBIL1-DDX39B locus and rs4947331 (PMeta= 9.85e?13) from NEU1 locus were found significantly associated. Identified genes are key regulators of cellular energy metabolism and associated with several immune mediated diseases. In silico functional annotation showed significant biological relevance of these novel markers and genes. FDI approved therapeutics against ATP6V1G2 and NEU1 are currently in use to treat chronic and inflammatory diseases. This study identified two pathogenic loci, originally involved in energy metabolism. Extensive investigation showed their synergistic role in CD pathogenesis by promoting immune mediated enteric inflammation. Proposed CD pathogenesis model in this study needs to be tested through tissue-on-chip and in vivo methods to ensure its translational application. � 2021, Indian Academy of Sciences.