Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells

Wu, Jun; Zhao, Meng; Jiang, Min; Pei, Rongjuan; Trippler, Martin; Broering, Ruth; Bucchi, Agnes; Sowa, Jan-Peter; Dittmer, Ulf; Yang, Dongliang; Roggendorf, Michael; Gerken, Guido; Lu, Mengji; Schlaak, Joerg F.

doi:10.1002/hep.22751

Cited by 293 publications

(254 citation statements)

References 147 publications

(209 reference statements)

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“…Previous studies demonstrate that HBV has evolved mechanisms to overcome TLR-mediated IFN signaling. 30 In accordance with these previous studies, the identification of an inhibitory role for HBx in virustriggered IFN signaling helps to explain how HBV evades the PRRmediated innate immune response, which results in viral evasion of the immune system and chronic infection of the host.…”

Section: Discussionsupporting

confidence: 70%

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Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

Wang

Mao

et al. 2010

Cell Mol Immunol

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Viral RNAs produced during viral infection are recognized by the cytoplasmic RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). A central adapter protein downstream of RIG-I and MDA5 is the mitochondrial membrane protein virus-induced signaling adaptor (VISA), which mediates the induction of type I interferons (IFNs) through the activation of transcription factors such as nuclear factor-kappaB (NF-kB) and IFN-regulatory factor-3 (IRF3). Here we found that hepatitis B virus (HBV)-encoded X protein (HBx) acts as an inhibitor of virus-triggered IRF3 activation and IFN-b induction. Reporter and plaque assays indicate that HBx inhibits signaling by components upstream but not downstream of VISA. Immunoprecipitation experiments indicate that HBx interacts with VISA and disrupts the association of VISA with its upstream and downstream components. These findings suggest that HBx acts as a suppressor of virus-triggered induction of type I IFNs, which explains the observation that HBV causes transient and chronic infection in hepatocytes but fails to activate the pattern recognition receptor-mediated IFN induction pathways.

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Section: Discussionsupporting

confidence: 70%

“…29 The Wu group also determined that Toll-like receptors mediate IRF3 and IFN-b activation and can be inhibited by a high level of HBV replication in HBV-Met cells. 30 These results suggest that HBV has evolved mechanisms to overcome the innate immune response of the host cell.…”

Section: Introductionmentioning

confidence: 97%

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

Wang

Mao

et al. 2010

Cell Mol Immunol

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“…HBsAg, HBeAg and HBV virions may also inhibit the activation of liver NPCs by TLR3 ligands. 32 Coculture of hepatic NPC cell supernatants containing HBsAg, HBeAg and HBV virions resulted in abrogation of TLR-induced antiviral activity, correlating with decreased activation of IRF-3, NF-kB and ERK1/2 in NPCs. Our recent data suggested that HBsAg may trigger IL-10 production in hepatic cells and thereby, attenuate the TLR3-mediated activation of NPCs.…”

Section: Interaction Between Tlrs and Hbvmentioning

confidence: 93%

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Zhang

Yang

et al. 2014

Cell Mol Immunol

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It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus (HBV) infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors (TLRs) sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons (IFNs) and pro-inflammatory cytokines. Experimental results from in vitro and in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T-and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.

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“…In mice, hepatitis B surface antigens (HBsAg), hepatitis envelope antigen (HBeAg), and HBV virions are capable of inhibiting TLR-dependent pathways [25]. HBV-X protein directly degrades adaptor molecule MAVS, resulting in the inhibition of RIG-I-dependent signaling pathways [26].…”

Section: Pattern Recognition Receptors In Hbv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-k3), remains to be elucidated. Human BDCA3 ? DCs have also been shown to be a potent producer of IFN-k3 in HCV infection, suggesting the possibility that BDCA3 ? DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.

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Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells

Cited by 293 publications

References 147 publications

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Host–virus interactions in hepatitis B and hepatitis C infection

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