Innate immune control of HCV infection through the JAK/STAT signaling

© Digestive Medicine Research. All rights reserved. Dig Med Res 2020 | http://dx.doi. org/10.21037/dmr-2020-19 Hepatitis C virus (HCV) is a positive-strand RNA virus that frequently overcomes host innate and adaptive immune response leading to a stage of chronic HCV infection. The mechanisms through which HCV develops such a high rate of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) remain elusive. During HCV infection, the innate and adaptive immune responses are generated through a cascade of virus-host signaling (1,2). Hepatocytes quickly sense the conserved pathogen-associated molecular pattern (PAMP) receptors present in HCV (HCV genomic RNA, structural and non-structural proteins) by different pattern recognition receptors (PRRs) such as RIG-I, MDA5, and toll like receptors (TLRs) (3). The damage-associated molecular pattern (DAMP) released in response to cell death (called sterile agents) during integrated cellular stress and cell damage leads to an inflammatory response. The innate immune signaling pathways are amplified through the production of type 1 and type III interferon (IFN), interferon-stimulated genes (ISGs), and proinflammatory cytokines to eliminate the virus. The multifaceted host antiviral response suppresses viral replication but cannot eradicate it completely in most cases. Only 25% of HCVinfected individuals resolve infection naturally, whereas the majority of the cases develop chronic stage of infection (3,4). Although HCV is a curable disease, the mechanism of innate immune activation that controls virus replication and viral clearance is unknown. This knowledge is essential to develop novel therapeutic strategies to control emerging new RNA virus infections such as SARS-COV-2. Many ear l ier s tudies have demonstrated HCV infection using primary human hepatocytes (PHH), human pluripotent stem cells, and induced pluripotent stem cells (5-8). All these primary non-transformed cells are permissive for HCV infection. However, these model systems support a low-level of HCV replication. Therefore, the Huh-7.5 cell line was used extensively in the past to study virus-host interaction. Carpentier et al. reported a new HCV infection model using human stem cell-derived hepatocyte-like cells (HLCs) (9). This model was used to understand the mechanism by which innate immune response controls HCV clearance. We feel that this study brings some new information worth discussing that will have important implications for natural immune mechanisms. First, the authors determined that HLCs cells express the critical component of host innate immune signaling such as RIG-I-like receptors (RLRs) and TLRs. They also demonstrated that HLCs maintains a high-level replication of a unique HCV strain called JC1 and the replication declines with innate immune activation. This model system seems appropriate to address the molecular mechanisms of innate immune activation. The authors found that host cell sensing of HCV through RIG-I and MDA5 results in the production of type I and type III IFN. The endogenously produced type I and type III IFN in the infected culture requires the JAK-STAT feedback loop Editorial Commentary