Interferon-induced immune signatures are associated with suppression of HEV infection in porcine cell culture models
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ABSTRACT:
ORGANISM(S): Sus scrofa
PROVIDER: GSE295453 | GEO | 2026/07/01
REPOSITORIES: GEO
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Project description:Background & Aims: Other than hepatitis B or C virus infection, Hepatitis E virus (HEV) infection is generally asymptomatic or leads to acute and self-limiting hepatitis. However, the mechanism of host cell defense against HEV is unclear. Viruses are known to perturb host cellular metabolism to enable their replication and spread. AMP-activated protein kinase (AMPK) activation is crucial for the regulation of cell homeostasis. We thus investigated the role of AMPK in HEV infection. Methods: Huh7, THP1 and HepG2 cells inoculated with infectious HEV viral particle or Huh7 and organoids transfected with in vitro generated subgenomic or full-length GT3 (Kernow-C1 p6 strain) HEV RNA, namely, p6Luc or p6 were used to model HEV infection. Viral replication and genes expression were quantified. Activation of AMPK, innate immune response and autophagy process were assessed. Results: We found HEV infection can trigger AMPK activation by phosphorylation of AMPK at threonine 172 by transfecting HEV viral RNA into host cells or inoculating host cells with infectious HEV viral particle. The activation of AMPK is associated with HEV induced mitochondrial damage and ATP deficiency. Pharmacological activation of AMPK using 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) attenuated HEV replication, which was reversed by an AMPK inhibitor (compound C). Lentivirus-mediated knockdown of AMPK provided further evidence that AMPK has an antiviral effect on HEV replication. These results suggested that AMPK activation is a potent strategy of host cells for HEV clearance. Consistent with its antiviral effect, AMPK activation potentiated the expression of genes with antiviral properties (e.g., IFNs, ISG15, and IRF9) and inhibited inflammatory response (e.g., NF-KB NLRP3 and IL-1β). Meanwhile, HEV and activated AMPK also decreased autophagosome accumulation by decreasing induction of autophagy and autophagic degradation. Consistently, we found inhibition of AMPK efficiently augmented HEV induced autophagosome accumulation, evidenced by a marked increase in LC3II. Our previous study showed that rapamycin, an activator of autophagic induction by inhibiting mTOR, and Bafilomycin A1, an inhibitor of autophagic degradation, has a potent pro-HEV effect under AICAR treatment. Moreover, Wortmannin inhibiting autophagic induction recover AMPK inhibitor induced HEV replication. Together, these results suggested that HEV induced AMPK activation can serve to protect HEV infected cells from HEV infection by attenuating autophagosome and promoting innate immunity. Conclusions: Here we show that HEV infection can activate AMPK phosphorylation, which attenuates autophagosome accumulation and increases innate immune signaling. Thus, the AMPK activation in response to HEV infection is critical in host cells for rapid viral clearance by coordinating autophagic process and establishing persistent antiviral immunity.
2024-03-31 | GSE262469 | GEO
Project description:Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders. Samples were treated with JFHA, and IL28b respectively with three biological replication.
2013-08-16 | E-GEOD-31455 | biostudies-arrayexpress
Project description:Influenza A virus has a broad cellular tropism in the respiratory tract. Infected epithelial cells sense the infection and initiate an antiviral response. To define the antiviral response at the earliest stages of infection we used two different single cycle replication reporter viruses. These tools demonstrated heterogeneity in virus replication levels in vivo. Transcriptional profiling demonstrated tiers of interferon stimulated gene responses that were dependent on the magnitude of virus replication. Uninfected cells and cells with blunted replication expressed a distinct and potentially protective ISG signature. Finally, we used these single cycle reporter viruses to determine the antiviral landscape during virus spread, which unveiled disparate protection mediated by IFN. Together these results highlight the complexity of virus-host interactions within the infected lung and suggest that magnitude and round of replication tune the antiviral response.
2018-09-20 | GSE112794 | GEO
Project description:A significant number of pandemics, endemics and even sporadic outbreaks trace back to zoonotic spillovers of emerging RNA viruses. Especially, zoonotic infections with the distantly related hepatitis E virus (HEV, species Paslahepevirus balayani) from various animal origins, such as pigs, deer, wild boar, rabbits and camelids, are well-documented and account for 20 million acute hepatitis cases each year. The detection of HEV RNA in rats surrounding pig farms suggest that they serve as an additional reservoir and source of zoonotic HEV infection. Moreover, the rising number of zoonotic spillover events with the distantly related rat hepatitis E virus (ratHEV, species Rocahepevirus ratti) underscores the urgent need to elucidate the role of rats as a reservoir for HEV infection and in the transmission dynamics of viruses within the family Hepeviridae. Herein, we introduce a novel HEV reverse zoonosis model based on the infection of rat liver cells, which supports completion of the entire HEV replication cycle. RNA sequencing analyses unraveled distinct host responses to HEV infection characterized by minimal activation of innate immune responses. Importantly, host-directed antivirals targeting entry factors previously identified in human host cells effectively restricted HEV infection in rat liver cells. Furthermore, human-specific genomic rearrangements conferred increased fitness across human and rat hepatoma cells. In conclusion, our study indicates conserved viral replication mechanisms of HEV between rats and humans, providing valuable insights into the molecular mechanisms of zoonotic spillover across species.
2026-05-01 | GSE329031 | GEO
Project description:Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders. Samples were treated with IFN, IL28b and T-PolyC after 6 or 24 hours respectively
2012-03-09 | E-GEOD-31264 | biostudies-arrayexpress
Project description:Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders. Samples were treated with IFN or IL28b after 6 or 24 hours with three replications
2012-03-09 | E-GEOD-31193 | biostudies-arrayexpress
Project description:We investigated the roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus (DENV). Double-deficient Irf-3-/-7-/- mice infected with the DENV2 strain S221 possessed 1,000-150,000 fold higher levels of viral RNA than wild-type and single-deficient mice 24 hours after infection; however, they remained resistant to lethal infection. IFN-α/β was induced similarly in wild-type and Irf-3-/- mice post DENV infection, whereas in the Irf-7-/- and Irf-3-/-7-/- mice, significantly low levels of IFN-α/β expression was observed within 24 hours post-infection. IFN-stimulated gene (ISG) induction was also delayed in Irf-3-/-7-/- mice relative to wild-type and single-deficient mice. In particular, Cxcl10 and Ifnα2 were rapidly induced independently of both IRF-3 and IRF-7 in the Irf-3-/-7-/- mice with DENV infection. Higher levels of serum IFN-γ, IL-6, CXCL10, IL-8, IL-12 p70, and TNF were also observed in Irf-3-/-7-/- mice 24 hours after infection, at which time point viral titers peaked and started to be cleared. Antibody-mediated blockade experiments revealed that IFN-γ, CXCL10, and CXCR3 function to restrict DENV replication in Irf-3-/-7-/- mice. Additionally, the ISGs Cxcl10, Ifit1, Ifit3, and Mx2 can be induced via an IRF-3- and IRF-7-independent pathway that does not involve IFN-γ signaling for protection against DENV. Collectively, these results demonstrate that IRF-3 and IRF-7 are redundant, albeit IRF-7 plays a more important role than IRF-3 in inducing the initial IFN-α/β response; only the combined actions of IRF-3 and IRF-7 are necessary for efficient control of early DENV infection; and the late, IRF-3- and IRF-7-independent pathway contributes to anti-DENV immunity. To identify the antiviral genes that are controlled by IRF-3 and IRF-7 signaling during DENV infection, we examined a panel of ISG expression in the spleens of wild-type, Irf-3-/-, Irf-7-/- and Irf-3-/-7-/- mice at 12 or 24 hours after DENV infection using a quantitative PCR array kit. The fold changes in expression of 55 genes from infected mice were normalized to that of strain-matched naïve mice.
2013-08-15 | E-GEOD-49871 | biostudies-arrayexpress
Project description:Effective anti-viral immunity depends on the ability of infected cells or cells triggered with virus-derived nucleic acids to produce type I interferon (IFN), which activates transcription of numerous antiviral genes. However, disproportionately strong or chronic IFN expression is a common cause of inflammatory and autoimmune diseases. Here we describe an epigenetic mechanism that determines cell-type specific differences in IFN and IFN-stimulated gene expression in response to exogenous signals. We identify di-methylation of histone H3 at lysine 9 (H3K9me2) as a suppressor of IFN and IFN-inducible antiviral gene expression. We show that levels of H3K9me2 at IFN and IFN stimulated genes (ISG) correlate inversely with the scope and amplitude of IFN and ISG expression in fibroblasts and dendritic cells. Accordingly, genetic ablation or pharmacological inactivation of lysine methyltransferase G9a, which is essential for the generation of H3K9me2, resulted in phenotypic conversion of fibroblasts into highly potent IFN-producing cells and rendered these cells resistant to pathogenic RNA viruses. In summary, our studies implicate H3K9me2 and enzymes controlling its abundance as key regulators of innate antiviral immunity. Examination of epigenetic modifications in WT and G9a deficient MEFs and splenic DCs
2012-03-02 | E-GEOD-22102 | biostudies-arrayexpress
Project description:Effective anti-viral immunity depends on the ability of infected cells or cells triggered with virus-derived nucleic acids to produce type I interferon (IFN), which activates transcription of numerous antiviral genes. However, disproportionately strong or chronic IFN expression is a common cause of inflammatory and autoimmune diseases. Here we describe an epigenetic mechanism that determines cell-type specific differences in IFN and IFN-stimulated gene expression in response to exogenous signals. We identify di-methylation of histone H3 at lysine 9 (H3K9me2) as a suppressor of IFN and IFN-inducible antiviral gene expression. We show that levels of H3K9me2 at IFN and IFN stimulated genes (ISG) correlate inversely with the scope and amplitude of IFN and ISG expression in fibroblasts and dendritic cells. Accordingly, genetic ablation or pharmacological inactivation of lysine methyltransferase G9a, which is essential for the generation of H3K9me2, resulted in phenotypic conversion of fibroblasts into highly potent IFN-producing cells and rendered these cells resistant to pathogenic RNA viruses. In summary, our studies implicate H3K9me2 and enzymes controlling its abundance as key regulators of innate antiviral immunity. Examination of gene expression in response to PolyI:C in WT and G9a deficient DCs
2012-03-02 | E-GEOD-24774 | biostudies-arrayexpress
Project description:Effective anti-viral immunity depends on the ability of infected cells or cells triggered with virus-derived nucleic acids to produce type I interferon (IFN), which activates transcription of numerous antiviral genes. However, disproportionately strong or chronic IFN expression is a common cause of inflammatory and autoimmune diseases. Here we describe an epigenetic mechanism that determines cell-type specific differences in IFN and IFN-stimulated gene expression in response to exogenous signals. We identify di-methylation of histone H3 at lysine 9 (H3K9me2) as a suppressor of IFN and IFN-inducible antiviral gene expression. We show that levels of H3K9me2 at IFN and IFN stimulated genes (ISG) correlate inversely with the scope and amplitude of IFN and ISG expression in fibroblasts and dendritic cells. Accordingly, genetic ablation or pharmacological inactivation of lysine methyltransferase G9a, which is essential for the generation of H3K9me2, resulted in phenotypic conversion of fibroblasts into highly potent IFN-producing cells and rendered these cells resistant to pathogenic RNA viruses. In summary, our studies implicate H3K9me2 and enzymes controlling its abundance as key regulators of innate antiviral immunity. Examination of gene expression in response to PolyI:C in WT and G9a deficient MEFs
2012-03-02 | E-GEOD-24776 | biostudies-arrayexpress