Hepatitis E genotype 4 virus from feces of monkeys infected experimentally can be cultured in PLC/PRF/5 cells and upregulate host interferon-inducible genes

Zhang, Feng; Qi, Ying; Harrison, Tim J.; Luo, Baobin; Zhou, Yan; Li, Xiuhua; Song, Aijing; Huang, Weijin; Wang, Youchun

doi:10.1002/jmv.24014

Cited by 30 publications

(26 citation statements)

References 40 publications

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“…In addition to HCV or NDV infection, several infections by WNV, hepatitis E virus, influenza A virus, Japanese encephalitis virus, and Sindbis virus are capable of upregulation of human ISG12a or murine Ifi27 (17,27,(39)(40)(41), which suggests that ISG12a/Ifi27 may play a vital role in antiviral innate immunity. Actually, we and other groups have determined the antiviral effects of ISG12a/IFI27 on HCV, NDV, WNV, and mouse hepatitis virus (MHV) infection in vitro or in vivo, though the underlying mechanisms remain unknown (22,24,26,27).…”

Section: Discussionmentioning

confidence: 99%

ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

Xue

Yang

Wang

et al. 2016

J Virol

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Interferons (IFNs) restrict various kinds of viral infection via induction of hundreds of IFN-stimulated genes (ISGs), while the functions of the majority of ISGs are broadly unclear. Here, we show that a high-IFN-inducible gene, ISG12a (also known as IFI27), exhibits a nonapoptotic antiviral effect on hepatitis C virus (HCV) infection. Viral NS5A protein is targeted specifically by ISG12a, which mediates NS5A degradation via a ubiquitination-dependent proteasomal pathway. K374R mutation in NS5A domain III abrogates ISG12a-induced ubiquitination and degradation of NS5A. S-phase kinase-associated protein 2 (SKP2) is identified as an ubiquitin E3 ligase for NS5A. ISG12a functions as a crucial adaptor that promotes SKP2 to interact with and degrade viral protein. Moreover, the antiviral effect of ISG12a is dependent on the E3 ligase activity of SKP2. These findings uncover an intriguing mechanism by which ISG12a restricts viral infection and provide clues for understanding the actions of innate immunity. IMPORTANCE Upon virus invasion, IFNs induce numerous ISGs to control viral spread, while the functions of the majority of ISGs are broadlyunclear. The present study shows a novel antiviral mechanism of ISGs and elucidated that ISG12a recruits an E3 ligase, SKP2, for ubiquitination and degradation of viral protein and restricts viral infection. These findings provide important insights into exploring the working principles of innate immunity.

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Section: Discussionmentioning

confidence: 99%

ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

Xue

Yang

Wang

et al. 2016

J Virol

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“…The HEV ORF3 protein, on the other hand, has been reported to enhance IFN production [20]. HEV also induced ISG expression in PLC/PRF/5 human hepatoma cells [21] and in A549 human lung epithelial cells [22]. Relevance of these observations to natural infection is uncertain, however, as most of studies were not conducted in hepatocyte cell lines and/or relied on overexpression of viral proteins.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis E virus persists in the presence of a type III interferon response

Yin

Ambardekar

et al. 2017

PLoS Pathog

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The RIG-I-like RNA helicase (RLR)-mediated interferon (IFN) response plays a pivotal role in the hepatic antiviral immunity. The hepatitis A virus (HAV) and the hepatitis C virus (HCV) counter this response by encoding a viral protease that cleaves the mitochondria antiviral signaling protein (MAVS), a common signaling adaptor for RLRs. However, a third hepatotropic RNA virus, the hepatitis E virus (HEV), does not appear to encode a functional protease yet persists in infected cells. We investigated HEV-induced IFN responses in human hepatoma cells and primary human hepatocytes. HEV infection resulted in persistent virus replication despite poor spread. This was companied by a type III IFN response that upregulated multiple IFN-stimulated genes (ISGs), but type I IFNs were barely detected. Blocking type III IFN production or signaling resulted in reduced ISG expression and enhanced HEV replication. Unlike HAV and HCV, HEV did not cleave MAVS; MAVS protein size, mitochondrial localization, and function remained unaltered in HEV-replicating cells. Depletion of MAVS or MDA5, and to a less extent RIG-I, also diminished IFN production and increased HEV replication. Furthermore, persistent activation of the JAK/STAT signaling rendered infected cells refractory to exogenous IFN treatment, and depletion of MAVS or the receptor for type III IFNs restored the IFN responsiveness. Collectively, these results indicate that unlike other hepatotropic RNA viruses, HEV does not target MAVS and its persistence is associated with continuous production of type III IFNs.

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“…In cell culture, the response of HEV infection to IFN treatment is moderate . Only IFNα exerts a considerable anti‐HEV effect; whereas other types, including IFNβ, IFNγ, IFNλ1, IFNλ2, and IFNλ3, do not show clear antiviral activity against HEV .…”

Section: Immune‐based Therapies For Hevmentioning

confidence: 99%

“…The novel ORF4 protein (nt 2835-3308), which is overlapped with ORF1, is only identified in genotype 1 IFN production may subsequently block the induction of ISG expression. However, in vitro cell culture studies 14,19 as well as studies in mice with humanized liver 20 demonstrated ISG induction upon HEV infections. These results indicate that HEV has developed strategies to dampen IFN induction, but not a complete inhibition.…”

Section: Induction and Antagonism Of Ifns By Hevmentioning

confidence: 99%

“…In cell culture, the response of HEV infection to IFN treatment is moderate. 14,19,24,98,99 Only IFNα exerts a considerable anti-HEV effect 24,100 ; whereas other types, including IFNβ, IFNγ, IFNλ1, IFNλ2, and IFNλ3, do not show clear antiviral activity against HEV. 24 HEV blocks IFNα-induced ISG expression via inhibition of STAT1 phosphorylation mediated by ORF3 protein.…”

Section: Ifn Treatmentmentioning

confidence: 99%

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Immunity against hepatitis E virus infection: Implications for therapy and vaccine development

Hakim

Ikram

Zhou

et al. 2017

Reviews in Medical Virology

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Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis worldwide and an emerging cause of chronic infection in immunocompromised patients. As with viral infections in general, immune responses are critical to determine the outcome of HEV infection. Accumulating studies in cell culture, animal models and patients have improved our understanding of HEV immunopathogenesis and informed the development of new antiviral therapies and effective vaccines. In this review, we discuss the recent progress on innate and adaptive immunity in HEV infection, and the implications for the devolopment of effective vaccines and immune-based therapies.

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Hepatitis E genotype 4 virus from feces of monkeys infected experimentally can be cultured in PLC/PRF/5 cells and upregulate host interferon-inducible genes

Cited by 30 publications

References 40 publications

ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

Hepatitis E virus persists in the presence of a type III interferon response

Immunity against hepatitis E virus infection: Implications for therapy and vaccine development

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