The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response

Wang, Wenshi; Wang, Yijin; Qu, Changbo; Wang, Shan; Zhou, Jianhua; Cao, Wanlu; Xu, Lei; Ma, Bo; Hakim, Mohamad S.; Yin, Yuebang; Li, Tiancheng; Peppelenbosch, Maikel P.; Zhao, Jingmin; Pan, Qiaoling

doi:10.1002/hep.29702

Cited by 44 publications

(32 citation statements)

References 42 publications

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“…We further demonstrated that the loss of the poly(A) tail in HEV SL3 significantly reduced the IFN induction potential of SL3, although it did not completely abolish its IFN induction potential. This was in corroboration with a previous study which demonstrated the IFN induction potential by HEV full-length genomic RNA was independent of the poly(A) tail (11). A poly(A) sequence of 50 nucleotides or more in length is known to induce an IFN response via RIG-I (26).…”

Section: Discussionsupporting

confidence: 91%

“…It was reported recently that the poly(A) tail is not essential for HEV RNA to induce the IFN response (11). Therefore, we also tested the potential of the SL3 without a poly(A) tail to induce an IFN response.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to playing an important role in viral replication, the UTRs of viral RNAs are also recognized by host PRRs such as RIG-I. The RIG-I-mediated innate immune response via IFN is known to play an important role in HEV infection (11,12,20). However, the HEV RNA PAMPs which are recognized by RIG-I are currently unknown.…”

Section: Discussionmentioning

confidence: 99%

“…The binding of RIG-I and viral RNA motifs signals the downstream transcription factor activation, which subsequently induces type I and/or III interferon (IFN) expression to establish an antiviral state (10). The RIG-I pathway has been shown to play an important role during HEV infection (11,12). However, the HEV RNA motifs that are recognized by RIG-I remain unknown.…”

mentioning

confidence: 99%

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The U-Rich Untranslated Region of the Hepatitis E Virus Induces Differential Type I and Type III Interferon Responses in a Host Cell-Dependent Manner

Sooryanarain

Heffron

Meng

2020

mBio

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Hepatitis E virus (HEV), a single-strand positive-sense RNA virus, is an understudied but important human pathogen. The virus can establish infection at a number of host tissues, including the small intestine and liver, causing acute and chronic hepatitis E as well as certain neurological disorders. The retinoic acid-inducible gene I (RIG-I) pathway is essential to induce the interferon (IFN) response during HEV infection. However, the pathogen-associated motif patterns (PAMPs) in the HEV genome that are recognized by RIG-I remain unknown. In this study, we first identified that HEV RNA PAMPs derived from the 3′ untranslated region (UTR) of the HEV genome induced higher levels of IFN mRNA, interferon regulatory factor-3 (IRF3) phosphorylation, and nuclear translocation than the 5′ UTR of HEV. We revealed that the U-rich region in the 3′ UTR of the HEV genome acts as a potent RIG-I PAMP, while the presence of poly(A) tail in the 3′ UTR further increases the potency. We further demonstrated that HEV UTR PAMPs induce differential type I and type III IFN responses in a cell type-dependent fashion. Predominant type III IFN response was observed in the liver tissues of pigs experimentally infected with HEV as well as in HEV RNA PAMP-induced human hepatocytes in vitro. In contrast, HEV RNA PAMPs induced a predominant type I IFN response in swine enterocytes. Taken together, the results from this study indicated that the IFN response during HEV infection depends both on viral RNA motifs and host target cell types. The results have important implications in understanding the mechanism of HEV pathogenesis. IMPORTANCE Hepatitis E virus (HEV) is an important human pathogen causing both acute and chronic viral hepatitis E infection. Currently, the mechanisms of HEV replication and pathogenesis remain poorly understood. The innate immune response acts as the first line of defense during viral infection. The retinoic acid-inducible gene I (RIG-I)-mediated interferon (IFN) response has been implicated in establishing antiviral response during HEV infection, although the HEV RNA motifs that are recognized by RIG-I are unknown. This study identified that the U-rich region in the 3′ untranslated region (UTR) of the HEV genome acts as a potent RIG-I agonist compared to the HEV 5′ UTR. We further revealed that the HEV RNA pathogen-associated motif patterns (PAMPs) induced a differential IFN response in a cell type-dependent manner: a predominantly type III IFN response in hepatocytes, and a predominantly type I IFN response in enterocytes. These data demonstrate the complexity by which both host and viral factors influence the IFN response during HEV infection.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The U-Rich Untranslated Region of the Hepatitis E Virus Induces Differential Type I and Type III Interferon Responses in a Host Cell-Dependent Manner

Sooryanarain

Heffron

Meng

2020

mBio

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“…Induction of type III IFNs in HepG2 cells infected with HEV3–Kernow depend on MAVS, MDA5, and to a lesser extent RIG-I [ 56 ]. However, RIG-I, MDA5, MAVS, or β-catenin knockout cells can still produce IFN in mouse embryonic fibroblast (MEF) cells, suggesting that HEV RNA is recognized by an as-yet-unknown cytosolic RNA sensor, at least in these cells [ 57 ]. IFN induction requires IRF3 and IRF7 in this system [ 57 ].…”

Section: Hev Rna Sensing By Infected Cellsmentioning

confidence: 99%

Hepatitis E Virus: How It Escapes Host Innate Immunity

et al. 2020

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Hepatitis E virus (HEV) is a leading cause of viral hepatitis in the world. It is usually responsible for acute hepatitis, but can lead to a chronic infection in immunocompromised patients. The host’s innate immune response is the first line of defense against a virus infection; there is growing evidence that HEV RNA is recognized by toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), leading to interferon (IFN) production. The IFNs activate interferon-stimulated genes (ISGs) to limit HEV replication and spread. HEV has developed strategies to counteract this antiviral response, by limiting IFN induction and signaling. This review summarizes the advances in our knowledge of intracellular pathogen recognition, interferon and inflammatory response, and the role of virus protein in immune evasion.

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A simplified qPCR method revealing tRNAome remodeling upon infection by genotype 3 hepatitis E virus

Zhang

et al. 2020

FEBS Letters

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The landscape of tRNA-viral codons regulates viral adaption at the translational level, presumably through adapting to host codon usage or modulating the host tRNAome. We found that the major zoonotic genotype of hepatitis E virus (HEV) has not adapted to host codon usage, prompting exploration of the effects of HEV infection on the host tRNAome. However, tRNAome quantification is largely impeded by the extremely short sequences of tRNAs and redundancy of tRNA genes. Here, we present a length-extension and stepwise simplified qPCR method that utilizes a universal DNA/RNA hybrid tRNA adaptor and degenerate primers. Using this novel methodology, we observe that HEV infection dramatically reprograms the hepatic tRNAome, which is likely to facilitate translation of viral RNAs. This tRNAome quantification method bears broad implications for future tRNA research and possibly tRNA-based diagnostics.

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The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response

Cited by 44 publications

References 42 publications

The U-Rich Untranslated Region of the Hepatitis E Virus Induces Differential Type I and Type III Interferon Responses in a Host Cell-Dependent Manner

The U-Rich Untranslated Region of the Hepatitis E Virus Induces Differential Type I and Type III Interferon Responses in a Host Cell-Dependent Manner

Hepatitis E Virus: How It Escapes Host Innate Immunity

A simplified qPCR method revealing tRNAome remodeling upon infection by genotype 3 hepatitis E virus

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