Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada.
Sci Rep. 2016 Dec 15;6:37433. doi: 10.1038/srep37433.
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 (JFH1) 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.
个体感染丙型肝炎病毒 (HCV) 后，发生进行性肝脏疾病（包括肝硬化和肝细胞癌 [HCC]）的风险很高。HCV 感染如何导致肝脏损伤多年来一直是人们关注的焦点，细胞凋亡已被提出作为一种作用机制。在这项研究中，我们采用组织培养适应株 HCV（JFH1）来检测 HCV 感染对 Huh-7.5 细胞中程序性细胞死亡（PCD）诱导的影响。我们发现 HCV 感染降低了受感染细胞群体的增殖率并诱导了 caspase-3 介导的细胞凋亡。然而，除了细胞凋亡，我们还观察到受感染的细胞发生 caspase-1 介导的细胞焦亡，这是由 NLRP3 炎性小体激活引起的。通过共培养 HCV 感染的 Huh-7.5 细胞和 HCV 非允许细胞系，我们还证明了未感染细胞中诱导了细胞凋亡和细胞焦亡。旁观者细胞凋亡，但旁观者细胞焦亡不需要感染细胞和旁观者细胞之间的细胞-细胞接触。总之，这些发现为 HCV 感染引起的细胞死亡机制提供了新的信息。观察到凋亡和细胞焦亡都可以在旁观者细胞中诱导，扩展了我们对 HCV 诱导肝脏发病机制的理解。
