MDA5 plays a critical role in interferon response during hepatitis C virus infection

Cao, Xuezhi; Ding, Qiang; Lu, Jie; Tao, Wanyin; Huang, Bing; Zhao, Yanan; Niu, Junqi; Liu, Yongjun; Zhong, Jin

doi:10.1016/j.jhep.2014.11.007

Cited by 83 publications

(99 citation statements)

References 39 publications

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“…In this haplotype, H843/ T946, the single-nucleotide polymorphism (SNP) rs3747517 encoding the H843 variant was also associated with spontaneous HCV clearance, whereas the SNP (rs1990760) encoding T946 was not. As discussed in an accompanying editorial, (2) if this finding is true, it broadens knowledge regarding the known innate immune response to HCV.…”

Section: To the Editormentioning

confidence: 82%

“…MDA5 recognizes HCV and plays an important role in initiating host innate immune response during HCV infection. (2) Egypt has the highest prevalence of HCV infection worldwide, with a seroprevalence ranging from 10% in children to 45% in adults. We recently refined the definition of the IL28B region associated with SC in Egypt in a sample of 261 individuals, 130 with SC and 131 with chronic infection.…”

Section: To the Editormentioning

confidence: 99%

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Refined association of melanoma differentiation‐associated gene 5 variants with spontaneous hepatitis C virus clearance in Egypt

et al. 2015

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commercial assays (14 of 343; 4.1%) were instead precisely resolved by HCV sequencing. As a whole, 28 of 343 (8.2%) patients achieved the correct genotyping assignment by sequencing. The overall percentage of genotype/subtype resolved by direct sequencing in the current study is similar to what has been found in other recent publications. (3,5) Our results emphasize the importance of dedicating time and effort for a proper genotype/subtype assignment before starting therapy. HCV sequencing allows precise subtype/genotype assignment, along with evaluation of natural resistance, thus reducing the risk of failure, especially in difficult-to-treat patients. The relatively low cost of sequencing (compared to therapy) should encourage studies aimed at better defining the advantage of its use at therapy baseline.

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Section: To the Editormentioning

confidence: 82%

Section: To the Editormentioning

confidence: 99%

Refined association of melanoma differentiation‐associated gene 5 variants with spontaneous hepatitis C virus clearance in Egypt

et al. 2015

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“…50% of the cells (data not shown). RIG-Ior MDA5-knockdown Huh7-MAVSR cells were generated as previously described (30). Statistical analysis.…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

“…Our data (not shown) also indicated that neither CH25H nor IFN-␤ induction was observed even at early time points (2, 4, 6, and 12 h) after HCVcc infection. We recently generated a Huh7 cell line that stably expresses a MAVS mutant resistant to the NS3/4A protease cleavage, designated Huh7-MAVSR, and HCV infection can induce a robust IFN response in this novel cell culture system (30). We infected Huh7-MAVSR cells with HCVcc (JFH1 strain) at a multiplicity of infection (MOI) of 2.…”

Section: Hc Inhibits Hcv Infectionmentioning

confidence: 99%

“…HCV 3=UTR and HCV infection can initiate innate immune cascade via pattern recognition receptor (PRR) RIG-I or MDA5, respectively (30,42). To determine which PRR is responsible for CH25H induction in response to HCV infection, we used CRISPR/Cas9 technology to knockdown RIG-I or MDA5 in Huh7-MAVSR cells as previously reported (30).…”

Section: Hc Inhibits Hcv Infectionmentioning

confidence: 99%

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Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

Tang

Tao

et al. 2015

J Virol

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Hepatitis C virus (HCV), a single-stranded positive-sense RNA virus of the Flaviviridae family, causes chronic liver diseases, including hepatitis, cirrhosis, and cancer. HCV infection is critically dependent on host lipid metabolism, which contributes to all stages of the viral life cycle, including virus entry, replication, assembly, and release. 25-Hydroxycholesterol (25HC) plays a critical role in regulating lipid metabolism, modulating immune responses, and suppressing viral pathogens. In this study, we showed that 25HC and its synthesizing enzyme cholesterol 25-hydroxylase (CH25H) efficiently inhibit HCV infection at a postentry stage. CH25H inhibits HCV infection by suppressing the maturation of SREBPs, critical transcription factors for host lipid biosynthesis. Interestingly, CH25H is upregulated upon poly(I·C) treatment or HCV infection in hepatocytes, which triggers type I and III interferon responses, suggesting that the CH25H induction constitutes a part of host innate immune response. To our surprise, in contrast to studies in mice, CH25H is not induced by interferons in human cells and knockdown of STAT-1 has no effect on the induction of CH25H, suggesting CH25H is not an interferon-stimulated gene in humans but rather represents a primary and direct host response to viral infection. Finally, knockdown of CH25H in human hepatocytes significantly increases HCV infection. In summary, our results demonstrate that CH25H constitutes a primary innate response against HCV infection through regulating host lipid metabolism. Manipulation of CH25H expression and function should provide a new strategy for anti-HCV therapeutics. IMPORTANCERecent studies have expanded the critical roles of oxysterols in regulating immune response and antagonizing viral pathogens. Here, we showed that one of the oxysterols, 25HC and its synthesizing enzyme CH25H efficiently inhibit HCV infection at a postentry stage via suppressing the maturation of transcription factor SREBPs that regulate lipid biosynthesis. Furthermore, we found that CH25H expression is upregulated upon poly(I·C) stimulation or HCV infection, suggesting CH25H induction constitutes a part of host innate immune response. Interestingly, in contrast to studies in mice showing that ch25h is an interferon-stimulated gene, CH25H cannot be induced by interferons in human cells but rather represents a primary and direct host response to viral infection. Our studies demonstrate that the induction of CH25H represents an important host innate response against virus infection and highlight the role of lipid effectors in host antiviral strategy. H epatitis C virus (HCV), a causative agent of acute and chronic liver diseases, is an enveloped positive-sense single-stranded RNA virus belonging to the family of Flaviviridae. Approximately 170 million people worldwide are infected with HCV. The tremendous progress has been achieved in the therapeutics of chronic hepatitis C thanks to the development of direct antiviral agents (DAAs), but the worldwide application of the...

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RNA‐virus proteases counteracting host innate immunity

Lei

Hilgenfeld

2017

FEBS Letters

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Virus invasion triggers host immune responses, in particular, innate immune responses. Pathogen‐associated molecular patterns of viruses (such as dsRNA, ssRNA, or viral proteins) released during virus replication are detected by the corresponding pattern‐recognition receptors of the host, and innate immune responses are induced. Through production of type‐I and type‐III interferons as well as various other cytokines, the host innate immune system forms the frontline to protect host cells and inhibit virus infection. Not surprisingly, viruses have evolved diverse strategies to counter this antiviral system. In this review, we discuss the multiple strategies used by proteases of positive‐sense single‐stranded RNA viruses of the families Picornaviridae, Coronaviridae, and Flaviviridae, when counteracting host innate immune responses.

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MDA5 plays a critical role in interferon response during hepatitis C virus infection

Cited by 83 publications

References 39 publications

Refined association of melanoma differentiation‐associated gene 5 variants with spontaneous hepatitis C virus clearance in Egypt

Refined association of melanoma differentiation‐associated gene 5 variants with spontaneous hepatitis C virus clearance in Egypt

Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection

RNA‐virus proteases counteracting host innate immunity

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