title: Innate immune responses in human hepatocyte-derived cell lines alter genotype 1 hepatitis E virus replication efficiencies.
abstract: Hepatitis E virus (HEV) is a significant health problem in developing countries causing sporadic and epidemic forms of acute viral hepatitis. Hepatitis E is a self-limiting disease; however, chronic HEV infections are being reported in immunocompromised individuals. The disease severity is more during pregnancy with high mortality (20-25%), especially in third trimester. Early cellular responses after HEV infection are not completely understood. We analyzed innate immune responses associated with genotype-I HEV replication in human hepatoma cell lines (Huh7, Huh7.5 and HepG2/C3A) using HEV replicon system. These cells supported HEV replication with different efficiencies due to the cell type specific innate immune responses. HepG2/C3A cells were less supportive to HEV replication as compared to Huh7.5 and S10-3 cells. Reconstitution of the defective RIG-I and TLR3 signaling in Huh7.5 cells enabled them to induce higher level antiviral responses and restrict HEV replication, suggesting the involvement of both RIG-I and TLR3 in sensing HEV RNA and downstream activation of interferon regulatory factor 3 (IRF3) to generate antiviral responses. Inhibition of IRF3 mediated downstream responses in HepG2/C3A cells by pharmacological inhibitor BX795 significantly improved HEV replication efficiency implying the importance of this study in establishing a better cell culture system for future HEV studies.
authors.affiliation: Hepatitis Division, National Institute of Virology, Microbial Containment Complex, Pashan, Pune, India.
authors.forename: Pradip B
authors.initials: PB
authors.lastname: Devhare
authors.affiliation: Hepatitis Division, National Institute of Virology, Microbial Containment Complex, Pashan, Pune, India.
authors.forename: Swapnil
authors.initials: S
authors.lastname: Desai
authors.affiliation: Hepatitis Division, National Institute of Virology, Microbial Containment Complex, Pashan, Pune, India.
authors.forename: Kavita S
authors.initials: KS
authors.lastname: Lole
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58 / Q000378:metabolism; D015870:Gene Expression; D016752:Hepatitis E virus / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D059467:Transcriptome; D014779:Virus Replication
chemical_list: D050835:Interferon Regulatory Factors; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58