Differential, Type I Interferon-Mediated Autophagic Trafficking of Hepatitis C Virus Proteins in Mouse Liver

Abstract

BACKGROUND & AIMS The hepatitis C virus (HCV) serine protease NS3/4A can cleave mitochondria-associated, anti-viral signaling protein (MAVS) and block retinoic acid-inducible gene I–mediated interferon (IFN) responses. Although this mechanism is thought to have an important role in HCV-mediated innate immunosuppression, its significance in viral persistence is not clear. METHODS We generated transgenic mice that express the HCV NS3/4A proteins specifically in the liver and challenged the animals with a recombinant vesicular stomatitis virus (VSV), a synthetic HCV genome, IFN-α, or IFN-β. We evaluated the effects of HCV serine protease on the innate immune responses and their interactions. RESULTS Expression of HCV NS3/4A resulted in cleavage of intrahepatic MAVS; challenge of transgenic mice with VSV or a synthetic HCV genome induced strong, type I IFN-mediated responses that were not significantly lower than those of control mice. Different challenge agents induced production of different ratios of IFN-α and -β, resulting in different autophagic responses and vesicular trafficking patterns of endoplasmic reticulum- and mitochondria-associated viral proteins. IFN-β promoted degradation of the viral proteins by the autolysosome. Variant isoforms of MAVS were associated with distinct, type I IFN-mediated autophagic responses; these responses have a role in trafficking of viral components to endosomal compartments that contain toll-like receptor -3. CONCLUSIONS IFN-β-mediates a distinct autophagic mechanism of anti-viral host defense. MAVS have an important role in type I IFN-induced autophagic trafficking of viral proteins.

Helicobacter pyloriinfection does not promote hepatocellular cancer in a transgenic mouse model of hepatitis C virus pathogenesis

“…66 In addition, through nucleotide-binding oligomerization domain 1, Ifnb1 also partially protects the infected host by decreasing H. pylori gastric colonization. 67 We observed significant upregulation of hepatic Ifnb1 in HT female Hp mice relative to WT female Hp mice suggesting that the HCV transgene contributed to a type I interferon response during H. pylori infection.…”

“…Five micrograms of RNA were converted to cDNA using High Capacity cDNA Reverse Transcription Kit (Applied Biosystems). Gastric and hepatic gene expression of Tumor necrosis factor (Tnf ) (Assay ID: Mm99999068_m1), Interferon gamma (Ifng) (Assay ID: Mm01168134_m1), Interferon β 1, fibroblast (Ifnb1) 66 (Assay ID: Mm00439546_s1), Interleukin 10 (Il10) (Assay ID: Mm01288386_m1) were measured using commercial TaqMan® primer-probe sets (Applied Biosystems-Life Technologies). The volume of each reaction consisted of 5 μl of sample cDNA, 4 μl of UltraPure™ Distilled Water (GibcoLife Technologies, 10977), 1 μl of primer-probe, and 10 μl of TaqMan® Fast Universal PCR Master Mix (2×) (Applied Biosystems, 4352042).…”

Bozepinib, a novel small antitumor agent, induces PKR-mediated apoptosis and synergizes with IFNα triggering apoptosis, autophagy and senescence

“…Consistent with the inability of MCF-7 cells to induce activation of caspase-3,28 pretreatment with the pan-caspase inhibitor Z-VAD did not affect the cell viability seen after the treatments (Figure 4D). Although it is known that autophagy is required for the production of IFNα by plasmacytoid dendritic cells during viral infection,40 and it has been recently shown that type I IFN induces autophagic trafficking of viral proteins of hepatitis C virus,41 the role of IFNα in the autophagy process is still unclear and knowledge is restricted to its antiviral function. Our results show, for the first time, evidence that IFNα is involved in the autophagy process in combination with an antitumor agent.…”

Pathogen-Induced Autophagy Signaling in Innate Immunity

“…Interestingly, distinct autophagic pathways were found to result in IFN-β or IFN-α signaling, in a model of viral infection [119]. IFN-β, which is first produced by hepatocytes upon viral detection (VSV or a synthetic HCV genome), was found to signal in order to orientate viral proteins towards an autophagic degradation, within autolysosomes.…”