title: Hepatitis C Virus Infection of Cultured Human Hepatoma Cells Causes Apoptosis and Pyroptosis in Both Infected and Bystander Cells.
abstract: Individuals infected with hepatitis C virus (HCV) are at high risk of developing progressive liver disease, including cirrhosis and hepatocellular carcinoma (HCC). How HCV infection causes liver destruction has been of significant interest for many years, and apoptosis has been proposed as one operative mechanism. In this study, we employed a tissue culture-adapted strain of HCV (JFH1T) to test effects of HCV infection on induction of programmed cell death (PCD) in Huh-7.5 cells. We found that HCV infection reduced the proliferation rate and induced caspase-3-mediated apoptosis in the infected cell population. However, in addition to apoptosis, we also observed infected cells undergoing caspase-1-mediated pyroptosis, which was induced by NLRP3 inflammasome activation. By co-culturing HCV-infected Huh-7.5 cells with an HCV-non-permissive cell line, we also demonstrated induction of both apoptosis and pyroptosis in uninfected cells. Bystander apoptosis, but not bystander pyroptosis, required cell-cell contact between infected and bystander cells. In summary, these findings provide new information on mechanisms of cell death in response to HCV infection. The observation that both apoptosis and pyroptosis can be induced in bystander cells extends our understanding of HCV-induced pathogenesis in the liver.
authors.affiliation: Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada.
authors.forename: H M
authors.initials: HM
authors.lastname: Kofahi
authors.affiliation: Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada.
authors.forename: N G A
authors.initials: NG
authors.lastname: Taylor
authors.affiliation: Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Hirasawa
authors.affiliation: Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada.
authors.forename: M D
authors.initials: MD
authors.lastname: Grant
authors.affiliation: Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada.
authors.forename: R S
authors.initials: RS
authors.lastname: Russell
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D024201:Bystander Effect; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000254:growth & development* / Q000472:pathogenicity; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D000069292:Pyroptosis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C505407:CASP3 protein, human; D053148:Caspase 3; D020170:Caspase 1