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.
Highlights
Individuals infected with hepatitis C virus (HCV) are at high risk of developing progressive liver disease, including cirrhosis and hepatocellular carcinoma (HCC)
We investigated the possibility that HCV itself causes cytopathic effects in the absence of immune cells
We found that HCV infection induced at least two forms of programmed cell death (PCD), those being apoptosis and pyroptosis
Summary
Individuals infected with hepatitis C virus (HCV) are at high risk of developing progressive liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Pyroptosis is a caspase-1-mediated, pro-inflammatory form of PCD12 It is initiated by a group of cytosolic sensors that belong to the NLR or HIN-200 receptor families The pro-inflammatory nature of pyroptosis suggests that this form of cell death could contribute to the chronic inflammation and pathogenesis associated with HCV infection. Activation of the NF-κB pathway, which is a hallmark of inflammatory response, can be involved in fibrogenesis as well as in initiation and progression of HCC in the chronically infected liver Inflammation and the release of ROS, inflammatory cytokines and chemokines by Kupffer cells are believed to activate hepatic stellate cells, thereby promoting liver fibrosis (reviewed in refs 29 and 30)
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