Chronic HCV infection and inflammation: Clinical impact on hepatic and extra-hepatic manifestations

Zampino, Rosa; Marrone, Aldo; Restivo, Luciano; Guerrera, Barbara; Sellitto, Andrea; Rinaldi, Luca; Romano, Ciro; Adinolfi, Luigi Elio

doi:10.4254/wjh.v5.i10.528

Cited by 189 publications

(170 citation statements)

References 137 publications

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“…HCV infection can induce inflammatory responses (38). In spite of this, HCV establishes persistent infections in the great majority of patients that it infects.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6

Chan

Lee

Narula

et al. 2016

J Virol

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Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an important adaptor molecule that mediates the TNFR family and interleukin-1 (IL-1)/Toll-like receptor (TLR) signaling cascades. These pathways are important for the host to control viral infections. In this report, we demonstrated that hepatitis C virus (HCV) depleted TRAF6 from its host cells through a posttranslational mechanism. This depletion was independent of proteasomes, as it was not affected by the proteasome inhibitor MG132, but it was suppressed by bafilomycin A1, which led to the association of TRAF6 with autophagosomes. As bafilomycin A1 is a vacuolar ATPase inhibitor that inhibits autophagic protein degradation, these results suggested that HCV depleted TRAF6 via autophagy. The degradation of TRAF6 was apparently mediated by the p62 sequestosome protein, which is a factor important for selective autophagy, as it could bind to TRAF6 and its silencing stabilized TRAF6. The depletion of TRAF6 suppressed activation of NF-B and induction of proinflammatory cytokines and enhanced HCV replication. In contrast, the overexpression of TRAF6 suppressed HCV replication. These results revealed a novel mechanism that was used by HCV to disrupt the host innate immune responses for viral replication and persistence. IMPORTANCEHCV can cause severe liver diseases and is one of the most important human pathogens. It establishes chronic infections in the great majority of patients that it infects, indicating that it has evolved sophisticated mechanisms to evade host immunity. TRAF6 is an important signaling molecule that mediates activation of NF-B and expression of proinflammatory cytokines and interferons. In this study, we found that HCV infection suppressed the host innate immune response through the induction of autophagic degradation of TRAF6. This finding provided important information for further understanding how HCV evades host immunity to establish persistence.

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“…HCV infection can induce inflammatory responses (38). In spite of this, HCV establishes persistent infections in the great majority of patients that it infects.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6

Chan

Lee

Narula

et al. 2016

J Virol

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“…Neurocogni tive defects in chronic HCV infection independent of hepatic encephalopathy is increasingly reported in several studies [10,26,29] . It is however unclear if the CNS itself supports the viral replication.…”

Section: Replication Of Hcv In Brainmentioning

confidence: 99%

“…How HCV is correlated with extrahepatic complications is poorly understood. Nevertheless, chronic infections are cha racterized by hepatic and systemic inflammation through activation of several signaling pathways and through their effect of release of various cytokines and augmented oxidative stress [10] . HCV infection could directly or indirectly cause systemic inflammations by inducing immunological response to the disease and metabolic imbalance.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus and neurological damage

Mathew

Faheem

Ibrahim

et al. 2016

WJH

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Author contributions: Mathew S and Faheem M contributed equally to this manuscript; Qadri I conceived and designed the topic; Mathew S, Faheem M, Ibrahim SM, Iqbal W and Rauff B contributed to materials and wrote the paper; Faheem M, Ibrahim SM, Iqbal W, Rauff B, Fatima K and Qadri I contributed to proof reading of the manuscript.Supported by KACST large R and D grant to Ishtiaq Qadri (#162-34).Conflict-of-interest statement: Authors declare no conflict of interests for this article. AbstractChronic hepatitis C virus (HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders. REVIEWSubmit a

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“…Finally, given that HCV infection spurs liver inflammation 21 and IL-6 is a positive regulator of HAMP gene expression 15,22 we monitored IL-6 levels by qRT-PCR in co-cultured THP-1 and infected Huh7.5 cells, in the presence and absence of iron loading. IL-6 mRNA was originally noted in hepatoma cells at 12 h p.i., but was then decreased to background.…”

Section: Hamp Overexpression Enhances Hcv Translation and Replicationmentioning

confidence: 99%

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

et al. 2016

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Mechanisms that favor Hepatitis C virus (HCV) persistence over clearance are unclear, but involve defective innate immunity. Chronic infection is characterized by hepatic iron overload, hyperferraemia and hyperferittinaemia. Hepcidin modulates iron egress via ferroportin and its storage in ferritin. Chronic HCV patients have decreased hepcidin, while HCV replication is modified by HAMP silencing. We aimed to investigate interactions between HCV and hepcidin, during acute and chronic disease, and putative alterations in cellular iron homeostasis that enhance HCV propagation and promote viral persistence. Thus, we used HCV JFH-1-infected co-cultures of Huh7.5 hepatoma and THP-1 macrophage cells, HCV patients' sera and Huh7 hepcidin-expressing cells transfected with HCV replicons. Hepcidin levels were elevated in acutely infected patients, but correlated with viral load in chronic patients. HAMP expression was up-regulated early in HCV infection in vitro, with corresponding changes in ferritin and FPN. Hepcidin overexpression enhanced both viral translation and replication. In HCV-infected co-cultures, we observed increased hepcidin, reduced hepatoma ferritin and a concurrent rise in macrophaghic ferritin over time. Altered iron levels complemented amplified replication in hepatoma cells and one replication round in macrophages. Iron-loading of macrophages led to enhancement of hepatic HCV replication through reversed ferritin "flow." Viral transmissibility from infected macrophages to na€ ıve hepatoma cells was induced by iron. We propose that HCV control over iron occurs both by intracellular iron sequestration, through hepcidin, and intercellular iron mobilisation via ferritin, as means toward enhanced replication. Persistence could be achieved through HCV-induced changes in macrophagic iron that enhances viral replication in these cells.

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Chronic HCV infection and inflammation: Clinical impact on hepatic and extra-hepatic manifestations

Cited by 189 publications

References 137 publications

Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6

Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6

Hepatitis C virus and neurological damage

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

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