Biology subjects

Sarmah, D. T.

Publications and source records attributed to Sarmah, D. T..

3 recordsLinked to original sources

bioRxiv2024

Network controllability analysis reveals the antiviral potential of Etravirine against Hepatitis E Virus infection

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis in lower- and middle-income countries. HEV infection may lead to acute liver failure, chronic liver disease and high mortality in pregnant women. Antiviral therapy is not a standard treatment for HEV patients. Computational biology tools promise to revolutionize the antiviral drug discovery. Here, we analyzed the transcriptome data of HEV infected primary human hepatocyte (PHH)-cells through connectivity map database and applied control theory on functional network to identify antiviral targets against HEV. The above analyses predicted PKC{beta}, PKB/AKT and CK1{varepsilon} as potential antiviral targets against HEV. The antiviral function of PKB/AKT and CK1{varepsilon} was experimentally validated by using respective biochemical inhibitors in g3 (genotype 3)-HEV replicon and Huh7 cell-based model of g3 and g1-HEV infection. Further, knockdown of CK1{varepsilon} showed a similar effect. These data confirmed that CK1{varepsilon} is an antiviral target for HEV. At present, there are no FDA approved drugs targeting CK1{varepsilon}. Etravirine is an FDA approved non-nucleoside reverse transcriptase inhibitor drug, used for the treatment of Human immunodeficiency virus type 1 (HIV-1) infected patients. An in silico study predicted Etravirine to be a potent inhibitor of CK1{varepsilon}. Our experiments revealed potent antiviral activity of Etravirine against HEV, which was mediated via its ability to inhibit the activity of CK1{varepsilon}. Taken together, the current study demonstrates that PKB/AKT and CK1{varepsilon} are bonafide antiviral targets for HEV and paves the way for repurposing Etravirine for the treatment of HEV infected patients. ImportanceAntiviral treatment is not the standard care for acute viral hepatitis E patients. Unbiased identification of antiviral targets or large-scale screening of antiviral compounds against the hepatitis E virus (HEV) has not been reported. Here, computational biology approach was followed to unbiasedly identify antiviral targets of HEV. Transcriptome data of HEV infected primary human hepatocyte (PHH) cells were analyzed to identify modulators of the network and generate directional networks. Network controllability analysis identified PKC{beta}, PKB/AKT and CK1{varepsilon} as potential antiviral targets against HEV. Antiviral function of PKB/AKT and CK1{varepsilon} was confirmed using cell-based models of genotype 1 (g1)- and g3-HEV infection. Further experiments demonstrated the antiviral activity of Etravirine against HEV, mediated via its ability to inhibit the CK1{varepsilon} activity. Etravirine is an FDA approved non-nucleoside reverse transcriptase inhibitor, used for the treatment of Human immunodeficiency virus type-1 (HIV-1)-infected patients. This study reveals the potential of repurposing Etravirine for treatment of HEV patients and illustrate the importance of computational biology in antiviral drug discovery.

microbiology↗

bioRxiv2023

BAG6 is a novel player in controlling nonalcoholic steatohepatitis: result from a comprehensive in-silico study

Nonalcoholic steatohepatitis, or NASH, is a multifactorial disease characterized by hepatic lipid accumulation, inflammation, cell death, and fibrosis, and an efficacious pharmaceutical intervention for this is yet to be discovered. The present study aims to identify potential targets capable of reversing the disease-specific molecular alterations and elucidate their possible action mechanism. Our study uses combinations of different methods, such as genome-scale metabolic modelling, directional protein-protein interaction network, connectivity map, and network controllability, to identify potential targets in NASH. Our approach yielded three promising targets, BAG6, CASP3, and CYCS, and captured their effects on inflammation, fibrosis, steatosis, and apoptosis. The association of CASP3 and CYCS with NASH are already reported in the literature. So BAG6 was selected as a novel target. In the Huh-7 cell-line, its ablation reduced fatty acid accumulation and decreased levels of NASH-signature transcripts, supporting our hypothesis on BAG6 as a potential NASH target.

systems biology↗

bioRxiv2022

Bidirectional regulation between AP-1 and SUMO genes modulates inflammatory signaling during Salmonella Typhimurium infection

Gram-negative bacterium Salmonella Typhimurium (STm) is the causative agent of gastroenteritis. Among the various gut pathogens, STm is still one of the most frequent culprits posing a significant health challenge. STm utilizes its effector proteins to highjack host cell processes. Alteration of SUMOylation, a post-translational modification mechanism, is one such change caused by STm. STm mediated simultaneous downregulation of SUMO-pathway genes, Ubc9 and PIAS1, is required for an efficient infection. In the present study, the regulation of SUMO pathway genes during STm infection was investigated. Promoters of both UBC9 and PIAS1, were seen to harbor binding motifs of AP-1, Activator protein-1 (c-Jun:c-Fos heterodimers or c-Jun:c-Jun homodimers). Using electrophoretic mobility shift assays, a direct binding of c-Fos to the identified motifs was observed. Perturbation of c-Fos led to changes in expression of Ubc9 and PIAS1, while its SUMO-modifications resulted in differential regulation of its target genes. In line with this, STm infection of fibroblasts with SUMOylation deficient c-Fos (c-FOS-KOSUMO-def-FOS) resulted in uncontrolled activation of target genes, as revealed by 3mRNA-Seq analysis and mathematical modelling, resulting in massive activation of inflammatory pathways. Infection of c-FOS-KOSUMO-def-FOS cells favored STm replication, indicating misdirected immune mechanisms in these cells. Finally, chromatin Immuno-precipitation assays confirmed a context dependent differential binding and release of AP-1 to/from target genes due to its Phosphorylation and SUMOylation respectively. Overall, our data point towards existence of a bidirectional cross-talk between c-Fos and the SUMO pathway and highlighting its importance in AP-1 function relevant to STm infections and beyond. Author summaryFood borne infections caused Salmonella Typhimurium pose a major health challenge in developing and developed world. Unfortunately, many aspects of Salmonella-host crosstalk still remain unknown. In the current work, using sophisticated computational tools along with cell culture experiments and mathematical modeling, we demonstrate how Salmonella controls SUMOylation, a post-translational modification (PTM) pathway of host. SUMOylation governs fundamental processes of the host cell, and its alteration is required for a successful Salmonella infection. We show that SUMO-pathway genes, Ubc9 and Pias1, are direct target genes of AP-1 transcription factor. C-Fos, a component of AP-1 transcriptionally regulates SUMO-genes by binding to their promoters. During Salmonella infection, a selective activation of target genes of c-Fos was observed. The selective regulation of target genes relied on c-fos PTMs. Experimental perturbation of c-Fos PTMs led to global transcriptional dysregulation including immune hyperactivation. Thus, we show existence of a complex interplay between the SUMO-pathway genes and AP-1 transcription factors which mediate selective gene regulation during Salmonella infection.

microbiology↗