Human MxA protein participates to the interferon-related inhibition of hepatitis B virus replication in female transgenic mice

Peltekian, Cécile; Gordien, Emmanuel; Garreau, Florianne; Meas-Yedid, V.; Soussan, Patrick Ben; Willams, Virginie; Chaix, Marie‐Laure; Olivo‐Marin, Jean‐Christophe; Bréchot, Christian; Kremsdorf, Dina

doi:10.1016/j.jhep.2005.06.019

Cited by 29 publications

(23 citation statements)

References 40 publications

(38 reference statements)

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“…Among these ISGs, MxA and OAS1 are antiviral genes, whereas CXCL10 is a chemokine gene responsible for the recruitment of effector CD8 T cells and NK cells to the site of viral infection. MxA likely plays an important role in HBV infection because it has been shown to inhibit HBV replication (39,41,42). Our results show that knockdown of endogenous MxA reversed the inhibition of HBV replication mediated by MDA5 signaling (Fig.…”

Section: Discussionmentioning

confidence: 53%

“…Given that MxA is known to suppress HBV replication (39)(40)(41)(42) and that MxA expression is upregulated in cells cotransfected with the HBV replicative plasmid and the MDA5 expression plasmid (Fig. 5A, top panel), we examined whether MxA contributed to the suppression of HBV replication mediated by the MDA5 signaling pathway.…”

Section: Cotransfection Of Huh7 Cells With the Hbv Replicative Plasmimentioning

confidence: 99%

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Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Lu¹,

Liao

2013

The Journal of Immunology

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Retinoic acid–inducible gene-I (RIG-I) and melanoma differentiation–associated gene 5 (MDA5) belong to the RIG-I–like receptors family of pattern recognition receptors. Both RIG-I and MDA5 have been shown to recognize various viral RNAs, but whether they mediate hepatitis B virus (HBV) infection remains unclear. In this study, we demonstrated that the expression of MDA5, but not RIG-I, was increased in Huh7 cells transfected with the HBV replicative plasmid and in the livers of mice hydrodynamically injected with the HBV replicative plasmid. To further determine the effect of RIG-I–like receptors on HBV replication, we cotransfected the HBV replicative plasmid with RIG-I or MDA5 expression plasmid into Huh7 cells and found that MDA5, but not RIG-I at a similar protein level, significantly inhibited HBV replication. Knockdown of endogenous MDA5, but not RIG-I, in Huh7 cells transfected with the HBV replicative plasmid significantly increased HBV replication. Of particular interest, we found that MDA5, but not RIG-I, was able to associate with HBV-specific nucleic acids, suggesting that MDA5 may sense HBV. Finally, we performed in vivo experiments by hydrodynamic injection of the HBV replicative plasmid into wild-type, MDA5−/−, MDA5+/−, or RIG-I+/− mice, and found that MDA5−/− and MDA5+/− mice, but not RIG-I+/− mice, exhibited an increase of HBV replication as compared with wild-type mice. Collectively, our in vitro and in vivo studies both support a critical role for MDA5 in the innate immune response against HBV infection.

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Section: Discussionmentioning

confidence: 53%

Section: Cotransfection Of Huh7 Cells With the Hbv Replicative Plasmimentioning

confidence: 99%

Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Lu¹,

Liao

2013

The Journal of Immunology

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“…It was reported previously that the IFN-inducible protein MxA blocked HBV replication both in vitro and in vivo (11,29). However, it was also reported that IFN-␣ induced the suppression of HBV replication in MxA-deficient cells (34).…”

Section: Discussionmentioning

confidence: 94%

Inhibition of Hepatitis B Virus Replication by MyD88 Involves Accelerated Degradation of Pregenomic RNA and Nuclear Retention of Pre-S/S RNAs

Lin

Chen

et al. 2010

J Virol

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Myeloid differentiation primary response protein 88 (MyD88), which can be induced by alpha interferon (IFN-␣), has an antiviral activity against the hepatitis B virus (HBV). The mechanism of this antiviral activity remains poorly understood. Here, we report that MyD88 inhibited HBV replication in HepG2.2.15 cells and in a mouse model. The knockdown of MyD88 expression weakened the IFN-␣-induced inhibition of HBV replication. Furthermore, MyD88 posttranscriptionally reduced the levels of viral RNA. Remarkably, MyD88 accelerated the decay of viral pregenomic RNA in the cytoplasm. Mapping analysis showed that the RNA sequence located in the 5-proximal region of the pregenomic RNA was critical for the decay. In addition, MyD88 inhibited the nuclear export of pre-S/S RNAs via the posttranscriptional regulatory element (PRE). The retained pre-S/S RNAs were shown to degrade in the nucleus. Finally, we found that MyD88 inhibited the expression of polypyrimidine tract-binding protein (PTB), a key nuclear export factor for PRE-containing RNA. Taken together, our results define a novel antiviral mechanism against HBV mediated by MyD88.Hepatitis B virus (HBV) is a noncytopathic, enveloped virus with a circular, double-stranded DNA genome. It causes both acute and chronic infection of the human liver. Although a highly effective preventive vaccine is now available, HBV infection remains a major health problem worldwide. It is estimated that chronic HBV infection affects 350 to 400 million people globally, about a quarter of whom will eventually develop severe liver diseases, including liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC) (4).Current antiviral therapies involve the use of nucleoside analogs and alpha interferon (IFN-␣) (28). IFN-␣, a type I interferon, engages the IFN-␣ receptor complex to activate the Jak/Stat pathway and trigger the transcription of a diverse set of genes, referred to as IFN-stimulated genes (ISGs) (2, 40). In total, the gene products of ISGs establish an antiviral response in target cells (2, 40). IFN-␣ inhibits HBV replication through a variety of mechanisms. It was reported previously that IFN-␣ can suppress viral gene expression, prevent the formation of viral RNA-containing core particles, and reduce the accumulation of viral replicative intermediates (11,35,37,(46)(47)(48). Importantly, the precise antiviral mechanism of IFN-␣ and the biological functions of many ISGs have not been fully elucidated.Myeloid differentiation primary response protein 88 (MyD88) is a key adaptor in the signaling cascade of the innate immune response (22). We and others have shown that MyD88 expression can be induced by IFN-␣ and that MyD88 has an antiviral activity against HBV in hepatoma cells that is mediated by nuclear factor B (NF-B) activation (12, 25, 51, 52). To counteract its inhibition, the HBV polymerase dampens the activation of the MyD88 promoter by blocking the nuclear translocation of Stat1, thereby reducing IFN-␣-inducible MyD88 expression (50), further suggesting a critical rol...

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“…However, it is not known whether some IFN-stimulated genes (ISGs) are able to directly inhibit HBV replication. In an HBV transgenic mouse model, twenty-nine genes were identified to be associated with the IFN-induced inhibition of HBV replication [14] and four ISGs, APOBEC3C [15,16,17], MxA [18,19,20], TRIM22 [21] and IDO [22], are reported to mediate the anti-HBV effect of type I IFN. …”

Section: Introductionmentioning

confidence: 99%

Interferon-Induced Proteins with Tetratricopeptide Repeats 1 and 2 Are Cellular Factors That Limit Hepatitis B Virus Replication

Pei

Qin²,

Xiao-yong³

et al. 2013

J Innate Immun

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Interferon (IFN)-α is able to stimulate many cellular genes and inhibit the replication of various viruses. However, it is unknown whether some IFN-stimulated genes (ISGs) specifically inhibit hepatitis B virus (HBV) replication. Therefore, we attempted to identify ISGs with antiviral activities against HBV. Knockdown of IFN-induced proteins with tetratricopeptide repeats 1 and 2 (IFIT1 and IFIT2) in HepG2.2.15 led to markedly increased HBV replication. Consistently, this effect was verified by transient transfection with a replication-competent HBV clone in HepG2 and Huh7. However, IFN-α stimulation could override the knockdown by siRNAs and enhance the expression of IFIT1 and IFIT2, leading to reduced HBV replication. Silencing of IFIT1 or IFIT2 decreased the expression of the corresponding genes while other ISGs like MxA were not affected. Northern blot analysis showed that IFIT1 and IFIT2 knockdown slightly increased the levels of HBV 3.5, 2.4 and 2.1 kb transcripts, while IFIT1 and IFIT2 overexpression did not change their levels. Consistently, the reporter assays with HBV promoters demonstrated that IFIT1 and IFIT2 differentially but only modestly regulated HBV promoter activity. Thus, IFIT1 and IFIT2 contribute significantly to the regulation of HBV replication, likely at both transcriptional and posttranscriptional steps.

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Human MxA protein participates to the interferon-related inhibition of hepatitis B virus replication in female transgenic mice

Cited by 29 publications

References 40 publications

Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Inhibition of Hepatitis B Virus Replication by MyD88 Involves Accelerated Degradation of Pregenomic RNA and Nuclear Retention of Pre-S/S RNAs

Interferon-Induced Proteins with Tetratricopeptide Repeats 1 and 2 Are Cellular Factors That Limit Hepatitis B Virus Replication

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