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Emerging roles of interferon-stimulated genes in the innate immune response to hepatitis C virus infection.

ABSTRACT: Infection with hepatitis C virus (HCV), a major viral cause of chronic liver disease, frequently progresses to steatosis and cirrhosis, which can lead to hepatocellular carcinoma. HCV infection strongly induces host responses, such as the activation of the unfolded protein response, autophagy and the innate immune response. Upon HCV infection, the host induces the interferon (IFN)-mediated frontline defense to limit virus replication. Conversely, HCV employs diverse strategies to escape host innate immune surveillance. Type I IFN elicits its antiviral actions by inducing a wide array of IFN-stimulated genes (ISGs). Nevertheless, the mechanisms by which these ISGs participate in IFN-mediated anti-HCV actions remain largely unknown. In this review, we first outline the signaling pathways known to be involved in the production of type I IFN and ISGs and the tactics that HCV uses to subvert innate immunity. Then, we summarize the effector mechanisms of scaffold ISGs known to modulate IFN function in HCV replication. We also highlight the potential functions of emerging ISGs, which were identified from genome-wide siRNA screens, in HCV replication. Finally, we discuss the functions of several cellular determinants critical for regulating host immunity in HCV replication. This review will provide a basis for understanding the complexity and functionality of the pleiotropic IFN system in HCV infection. Elucidation of the specificity and the mode of action of these emerging ISGs will also help to identify novel cellular targets against which effective HCV therapeutics can be developed.

SUBMITTER: Wong MT

PROVIDER: S-EPMC4712384 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Emerging roles of interferon-stimulated genes in the innate immune response to hepatitis C virus infection.

Wong Mun-Teng MT Chen Steve S-L SS

Cellular & molecular immunology 20141229 1

Infection with hepatitis C virus (HCV), a major viral cause of chronic liver disease, frequently progresses to steatosis and cirrhosis, which can lead to hepatocellular carcinoma. HCV infection strongly induces host responses, such as the activation of the unfolded protein response, autophagy and the innate immune response. Upon HCV infection, the host induces the interferon (IFN)-mediated frontline defense to limit virus replication. Conversely, HCV employs diverse strategies to escape host inn ...[more]

PMID: 25544499

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Project description:Type I interferons (IFNs) are induced upon viral infection and important mediators of innate immunity. While there is 1 beta interferon (IFN-?) protein, there are 12 different IFN-? subtypes. It has been reported extensively that different viruses induce distinct patterns of IFN subtypes, but it has not been previously shown how the viral multiplicity of infection (MOI) can affect IFN induction. In this study, we discovered the novel finding that human U937 cells infected with 2 different concentrations of Sendai virus (SeV) induce 2 distinct type I IFN subtype profiles. Cells infected at the lower MOI induced more subtypes than cells infected at the higher MOI. We found that this was due to the extent of signaling through the IFN receptor (IFNAR). The cells infected at the lower viral MOI induced the IFNAR2-dependent IFN-? subtypes 4, 6, 7, 10, and 17, which were not induced in cells infected at higher virus concentrations. IFN-? and IFN-?1, -2, and -8 were induced in an IFNAR-independent manner in cells infected at both virus concentrations. IFN-?5, -14, -16, and -21 were induced in an IFNAR-dependent manner in cells infected at lower virus concentrations and in an IFNAR-independent manner in cells infected at higher virus concentrations. These differences in IFN subtype profiles in the 2 virus concentrations also resulted in distinct interferon-stimulated gene induction. These results present the novel finding that different viral MOIs differentially activate JAK/STAT signaling through the IFNAR, which greatly affects the profile of IFN subtypes that are induced.Type I IFNs are pleiotropic cytokines that are instrumental in combating viral diseases. Understanding how the individual subtypes are induced is important in developing strategies to block viral replication. Many studies have reported that different viruses induce distinct type I IFN subtype profiles due to differences in the way viruses are sensed in different cell types. However, we report in our study the novel finding that the amount of virus used to infect a system can also affect which type I IFN subtypes are induced due to the extent of activation of certain signaling pathways. These distinct IFN subtype profiles in cells infected at different MOIs are correlated with differences in interferon-stimulated gene induction, indicating that the same virus can induce distinct antiviral responses depending on the MOI. Because type I IFNs are used as therapeutic agents to treat viral diseases, understanding their antiviral mechanisms can enhance clinical treatments.

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Emerging roles of interferon-stimulated genes in the innate immune response to hepatitis C virus infection.

Publications

Emerging roles of interferon-stimulated genes in the innate immune response to hepatitis C virus infection.

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