Regulation of hepatic innate immunity by hepatitis C virus

Horner, Stacy M.; Gale, Michael

doi:10.1038/nm.3253

Cited by 253 publications

(295 citation statements)

References 116 publications

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“…In addition, antiviral immunity triggered by exosomal transfer of viral RNA to pDCs has been suggested in HCV infection (3). HCV persistence and pathology, depends on strategies evolved to avoid innate recognition in infected cells (2). It will become important to resolve how pathogenic (viral) RNAs are incorporated and transported via exosomes, as the packaging machineries of virion capsids are presumably lacking.…”

Section: Discussionmentioning

confidence: 99%

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Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Baglio¹,

Eijndhoven²,

Koppers-Lalić

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

144

145

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Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein-Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viraland exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5′ppp, in vitro transcripts, and coculture experiments, we established that 5′pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non-cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host-pathogen stand-off and may promote inflammatory disease.exosomes | EBV-EBER1 | innate sensing | dendritic cells | skin inflammation

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Section: Discussionmentioning

confidence: 99%

“…Some RNA viruses establish a chronic productive infection: for example, hepatitis C virus (HCV), which evolved strategies to escape from innate immune sensors contributing to its pathophysiology (2). Nevertheless HCV, an enveloped RNA virus, can be recognized by sensory plasmacytoid dendritic cells (pDCs) (3).…”

mentioning

confidence: 99%

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Baglio¹,

Eijndhoven²,

Koppers-Lalić

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

144

145

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“…Infected cells also use different cellular surveillance mechanisms to block virus replication and spread 6. One such mechanism involves the production of IFN, which directly inhibits virus replication 7. The other mechanism involves blocking the spread of infection by inducing p53‐mediated cellular apoptosis 8…”

Section: Introductionmentioning

confidence: 99%

“…Over the past several years, many investigators, including our own, showed that HCV‐associated ER stress induced an autophagy response, which results in impaired host innate immunity through blocking endogenous IFN production7, 9 and also escapes from exogenously added IFN‐α and ribavirin (RBV)‐based antiviral therapy through degradation of interferon‐alpha receptor 1 and RBV transporter 10, 11. In this report, we found that HCV infection induces chaperone‐mediated autophagy (CMA) as a cell survival mechanism to avoid the ER‐stress response.…”

Section: Introductionmentioning

confidence: 99%

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Aydın

Chatterjee

Chandra

et al. 2017

Hepatology Communications

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The mechanism why hepatitis C virus (HCV) clearance by direct‐acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)‐stress response. In this study, we examined whether HCV clearance by interferon‐alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone‐mediated autophagy (CMA) in infected primary human hepatocytes and Huh‐7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin‐3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome‐dependent mechanism because lysosome‐associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon‐alpha‐based antiviral therapies normalizes the ER‐stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV‐infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV‐induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER‐stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256‐269)

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“…The two key cellular sensors are Toll-like receptor 3 (TLR3), which senses doublestranded RNA (dsRNA) within endosomes, and the RNA helicase retinoic acid-inducible gene I (RIG-I), which senses intracellular double-stranded RNA or single-stranded viral RNA (Wang et al, 2009;Green et al, 2012Green et al, , 2014Li et al, 2012;Horner and Gale, 2013). Signaling initiated by TLR3 and RIG-I is transmitted through the adaptor proteins Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) and mitochondrial antiviral-signaling protein (MAVS) respectively, to interact with TNF receptor-associated factor 3 (TRAF3) and converge on the transcription factors, interferon regulatory factor 3 (IRF3) and NF-κB.…”

Section: Introductionmentioning

confidence: 99%

Asunaprevir Evokes Hepatocytes Innate Immunity to Restrict the Replication of Hepatitis C and Dengue Virus

Tsai¹,

Cheng²,

Lai³

et al. 2016

Journal of Hepatology

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Type I Interferon-mediated innate immunity against Flaviviridae, such as Hepatitis C virus (HCV) and Dengue virus (DENV), involves TLR3, RIG-I-like receptor (RLR) and JAK-STAT signal pathways. Asunaprevir is a newly developed HCV protease inhibitor for HCV treatment. Whether, asunaprevir activates innate immunity to restrict viral infection is unclear. Thus, this study investigates the effect of asunaprevir on innate immunity and its influence on HCV and DENV infection. Huh 7.5.1, Hep-G2 cells, JFH-1 infection model, and DENV-2 infection were used for the analysis. The activity of asunaprevir-regulated innate immunity signal pathway was assessed with IFN-β promoter or IFN-stimulated responsive element (ISRE) reporter assays and immunoblotting of key signal proteins. siRNA-mediated MAVS and TRIF knockdown of cells was performed to assess the effect of asunaprevir-regulated innate immunity against HCV and DENV. Asunaprevir treatment activated ISRE and IFN-β promoter-luciferase activities and signaling proteins in the JAK-STAT, MAVS, and TRIF pathways in Huh 7.5.1 cells. Asunaprevir-mediated signaling activation was decreased in MAVS-knockdown cells. Importantly, both RNA and protein levels of DENV-2 NS3 were decreased in asunaprevir-treated Huh 7.5.1 and HepG2 cells. In MAVS-knockdown cells, the restrictive effect of asunaprevir on HCV and DENV was attenuated. Our findings reveal an unexpected activity of asunaprevir, the activation of MAVS dependent innate immunity to restrict HCV and DENV infection.

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Regulation of hepatic innate immunity by hepatitis C virus

Cited by 253 publications

References 116 publications

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Asunaprevir Evokes Hepatocytes Innate Immunity to Restrict the Replication of Hepatitis C and Dengue Virus

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