Hepatitis E Virus Inhibits Type I Interferon Induction by ORF1 Products

Hepatitis E virus (HEV) is responsible for large waterborne epidemics of hepatitis in endemic countries and is an emerging zoonotic pathogen worldwide. In endemic regions, HEV-1 or HEV-2 genotypes are frequently associated with fulminant hepatitis in pregnant women, while with zoonotic HEV (HEV-3 and HEV-4), chronic cases of hepatitis and severe neurological disorders are reported. Hence, it is important to characterize the interactions between HEV and its host. Here, we investigated the ability of the non-structural polyprotein encoded by the first open reading frame (ORF1) of HEV to modulate the host early antiviral response and in particular the type I interferon (IFN-I) system. We found that the amino-terminal region of HEV-3 ORF1 (MetPCP), containing a putative methyltransferase (Met) and a papain-like cysteine protease (PCP) functional domain, inhibited IFN-stimulated response element (ISRE) promoter activation and the expression of several IFN-stimulated genes (ISGs) in response to IFN-I. We showed that the MetPCP domain interfered with the Janus kinase (JAK)/signal transducer and activator of transcription protein (STAT) signalling pathway by inhibiting STAT1 nuclear translocation and phosphorylation after IFN-I treatment. By contrast, MetPCP had no effect on STAT2 phosphorylation and a limited impact on the activation of the JAK/STAT pathway after IFN-II stimulation. This inhibitory function seemed to be genotype-dependent as MetPCP from HEV-1 had no significant effect on the JAK/STAT pathway. Overall, this study provides evidence that the predicted MetPCP domain of HEV ORF1 antagonises STAT1 activation to modulate the IFN response.

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Hepatitis E virus infection activates signal regulator protein α to down-regulate type I interferon

Immunologic Research ◽

10.1007/s12026-015-8729-y ◽

2015 ◽

Vol 64 (1) ◽

pp. 115-122 ◽

Cited By ~ 8

Author(s):

Fen Huang ◽

Chenchen Yang ◽

Wenhai Yu ◽

Yanhong Bi ◽

Feiyan Long ◽

...

Keyword(s):

Virus Infection ◽

Hepatitis E Virus ◽

Type I Interferon ◽

Hepatitis E ◽

Type I ◽

Regulator Protein

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The Amino-Terminal Region of Hepatitis E Virus ORF1 Containing a Methyltransferase (Met) and a Papain-Like Cysteine Protease (PCP) Domain Counteracts Type I Interferon Response

Viruses ◽

10.3390/v10120726 ◽

2018 ◽

Vol 10 (12) ◽

pp. 726 ◽

Cited By ~ 4

Author(s):

Eugénie Bagdassarian ◽

Virginie Doceul ◽

Marie Pellerin ◽

Antonin Demange ◽

Léa Meyer ◽

...

Keyword(s):

Cysteine Protease ◽

Hepatitis E Virus ◽

Type I Interferon ◽

Hepatitis E ◽

Terminal Region ◽

Janus Kinase ◽

Functional Domain ◽

Type I ◽

Amino Terminal ◽

Stat Pathway

Hepatitis E virus (HEV) is responsible for large waterborne epidemics of hepatitis in endemic countries and is an emerging zoonotic pathogen worldwide. In endemic regions, HEV-1 or HEV-2 genotypes are frequently associated with fulminant hepatitis in pregnant women, while with zoonotic HEV (HEV-3 and HEV-4), chronic cases of hepatitis and severe neurological disorders are reported. Hence, it is important to characterize the interactions between HEV and its host. Here, we investigated the ability of the nonstructural polyprotein encoded by the first open reading frame (ORF1) of HEV to modulate the host early antiviral response and, in particular, the type I interferon (IFN-I) system. We found that the amino-terminal region of HEV-3 ORF1 (MetYPCP), containing a putative methyltransferase (Met) and a papain-like cysteine protease (PCP) functional domain, inhibited IFN-stimulated response element (ISRE) promoter activation and the expression of several IFN-stimulated genes (ISGs) in response to IFN-I. We showed that the MetYPCP domain interfered with the Janus kinase (JAK)/signal transducer and activator of the transcription protein (STAT) signalling pathway by inhibiting STAT1 nuclear translocation and phosphorylation after IFN-I treatment. In contrast, MetYPCP had no effect on STAT2 phosphorylation and a limited impact on the activation of the JAK/STAT pathway after IFN-II stimulation. This inhibitory function seemed to be genotype-dependent, as MetYPCP from HEV-1 had no significant effect on the JAK/STAT pathway. Overall, this study provides evidence that the predicted MetYPCP domain of HEV ORF1 antagonises STAT1 activation to modulate the IFN response.

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RNA Helicase DDX3 Interacts with the Capsid Protein of Hepatitis E Virus and Plays an Indispensable Role in the Viral Replication

10.20944/preprints202012.0557.v1 ◽

2020 ◽

Author(s):

Shaoli Lin ◽

Peixi Chang ◽

Jia He ◽

Etienne Coyaud ◽

Brian Pierce ◽

...

Keyword(s):

Viral Replication ◽

Capsid Protein ◽

Hepatitis E Virus ◽

Direct Interaction ◽

Hepatitis E ◽

Rna Helicase ◽

Type I Interferons ◽

Type I ◽

Interferon Induction

DDX3 is an ATP-dependent RNA helicase involved in multiple cellular activities, including RNA metabolism and innate immunity. DDX3 is known to assist the replication of some viruses while restricting some others through direct interaction with the viral proteins. However, the role of DDX3 in the replication of the hepatitis E virus (HEV) is unknown. In this study, DDX3 is shown to interact with the HEV capsid protein and provide an indispensable role in HEV replication. The DDX3 C-terminal domain was demonstrated to interact with the capsid protein, which was previously demonstrated to inhibit the production of type I interferons. Knockdown of DDX3 compromised the capsid protein-mediated blockage of interferon induction. Notably, DDX3 silencing led to a significant reduction in HEV replication. Also, the ATPase activity of DDX3 is required for the HEV replication as an ATPase-null mutant DDX3 failed to rescue the viral replication in the DDX3-silenced cells. These results demonstrate a pro-viral role of DDX3 in HEV replication, providing further insights into the virus-cell interactions.

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ISG15 Modulates Type I Interferon Signaling and the Antiviral Response during Hepatitis E Virus Replication

Journal of Virology ◽

10.1128/jvi.00621-17 ◽

2017 ◽

Vol 91 (19) ◽

Cited By ~ 18

Author(s):

Harini Sooryanarain ◽

Adam J. Rogers ◽

Dianjun Cao ◽

Mary Etna R. Haac ◽

Yogesh A. Karpe ◽

...

Keyword(s):

Hepatitis E Virus ◽

Acute Viral Hepatitis ◽

Type I Interferon ◽

Organ Transplant ◽

Clinical Problem ◽

Antiviral Effect ◽

Hepatitis E ◽

Type I ◽

Solid Organ ◽

Type I Ifn

ABSTRACT Hepatitis E virus (HEV), a single-stranded positive-sense RNA virus, generally causes self-limiting acute viral hepatitis, although chronic HEV infection has recently become a significant clinical problem in immunocompromised individuals, especially in solid-organ transplant recipients. Innate immunity, via the type I interferon (IFN) response, plays an important role during the initial stages of a viral infection. IFN-stimulated gene 15 (ISG15), an IFN-induced ubiquitin-like protein, is known to have an immunomodulatory role and can have a direct antiviral effect on a wide spectrum of virus families. In the present study, we investigated the antiviral effect as well as the potential immunomodulatory role of ISG15 during HEV replication. The results revealed that HEV induced high levels of ISG15 production both in vitro (Huh7-S10-3 liver cells) and in vivo (liver tissues from HEV-infected pigs); however, ISG15 is not required for virus replication. We also demonstrated that ISG15 silencing potentiates enhanced type I IFN-mediated signaling, resulting in an increase in the type I IFN-mediated antiviral effect during HEV replication. This observed enhanced type I IFN signaling correlated with an increase in IFN-stimulated gene expression levels during HEV replication. Furthermore, we showed that PKR and OAS1 played important roles in the ISG15-mediated type I IFN sensitivity of HEV. Taken together, the results from this study suggest that ISG15 plays an important immunomodulatory role and regulates HEV sensitivity to exogenous type I IFN. IMPORTANCE Hepatitis E virus (HEV) infection typically causes self-limiting acute viral hepatitis. However, chronic HEV infection has recently become a significant clinical problem in immunocompromised patients. Pegylated interferon (IFN) has been used to treat chronic HEV infection in solid-organ transplant patients with some success. However, the mechanism behind the type I IFN-mediated antiviral effect against HEV remains unclear. This report demonstrates that ISG15 induced by HEV replication in Huh7-S10-3 human liver cells plays an immunomodulatory role by negatively regulating type I IFN signaling and, thus, HEV sensitivity to type I IFN. Our results also show that PKR and OAS1 play important roles in the ISG15-mediated type I IFN sensitivity of HEV.

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