The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway

Tali Lang, Camden Lo, Narelle Skinner, Stephen Locarnini, Kumar Visvanathan, Ashley Mansell

Research output: Contribution to journalArticleResearchpeer-review

116 Citations (Scopus)

Abstract

Viruses target innate immune pathways to evade host antiviral responses. Recent studies demonstrate a relationship between hepatitis B disease states and the host s innate immune response, although the mechanism of immunomodulation is unknown. In humans, the innate immune system recognizes pathogens via pattern recognition receptors such as the Toll-like receptors (TLR), initiating an anti-inflammatory responses. Previous studies have shown that both TLR expression and pro-inflammatory cytokine production is reduced in hepatitis B e antigen (hbeag)-positive patients compared to hbeag-negative patients following TLR stimulation. The aim of this study was to investigate interactions between TLR signaling pathways and the mature hbeag protein localized in the cytosol METHODS AND RESULTS: Our findings show that hbeag co-localizes with Toll/IL-1 receptor (TIR) -containing proteins TRAM, Mal and TLR2 at the sub-cellular level. Conversely, Hepatitis B core antigen did not co-localize with TIR proteins. Co-immunoprecipitation analysis further demonstrated hbeag interaction with TIR proteins Mal and TRAM, while a mutated form of hbeag ablated interaction with Mal and myd88. Importantly, hbeag was able to disrupt homotypic TIR:TIR interaction critical for TLR-mediated signalling. Finally, hbeag specifically suppressed TIR-mediated activation of the prototypic inflammatory transcription factors, NF-kappab and Interferon-beta promoter activity CONCLUSION: Our study provides the first molecular mechanism describing hbeag immunomodulation of innate immune signal transduction pathways via interaction and targeting of TLR-mediated signaling pathways. These finding suggest the mechanism as to how hbeag evades innate immune responses contributing to the pathogenesis of chronic hepatitis B infection and the establishment of viral persistence.
Original languageEnglish
Pages (from-to)762 - 769
Number of pages8
JournalJournal of Hepatology
Volume55
Issue number4
DOIs
Publication statusPublished - 2011

Cite this

Lang, Tali ; Lo, Camden ; Skinner, Narelle ; Locarnini, Stephen ; Visvanathan, Kumar ; Mansell, Ashley. / The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway. In: Journal of Hepatology. 2011 ; Vol. 55, No. 4. pp. 762 - 769.
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abstract = "Viruses target innate immune pathways to evade host antiviral responses. Recent studies demonstrate a relationship between hepatitis B disease states and the host s innate immune response, although the mechanism of immunomodulation is unknown. In humans, the innate immune system recognizes pathogens via pattern recognition receptors such as the Toll-like receptors (TLR), initiating an anti-inflammatory responses. Previous studies have shown that both TLR expression and pro-inflammatory cytokine production is reduced in hepatitis B e antigen (hbeag)-positive patients compared to hbeag-negative patients following TLR stimulation. The aim of this study was to investigate interactions between TLR signaling pathways and the mature hbeag protein localized in the cytosol METHODS AND RESULTS: Our findings show that hbeag co-localizes with Toll/IL-1 receptor (TIR) -containing proteins TRAM, Mal and TLR2 at the sub-cellular level. Conversely, Hepatitis B core antigen did not co-localize with TIR proteins. Co-immunoprecipitation analysis further demonstrated hbeag interaction with TIR proteins Mal and TRAM, while a mutated form of hbeag ablated interaction with Mal and myd88. Importantly, hbeag was able to disrupt homotypic TIR:TIR interaction critical for TLR-mediated signalling. Finally, hbeag specifically suppressed TIR-mediated activation of the prototypic inflammatory transcription factors, NF-kappab and Interferon-beta promoter activity CONCLUSION: Our study provides the first molecular mechanism describing hbeag immunomodulation of innate immune signal transduction pathways via interaction and targeting of TLR-mediated signaling pathways. These finding suggest the mechanism as to how hbeag evades innate immune responses contributing to the pathogenesis of chronic hepatitis B infection and the establishment of viral persistence.",
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The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway. / Lang, Tali; Lo, Camden; Skinner, Narelle; Locarnini, Stephen; Visvanathan, Kumar; Mansell, Ashley.

In: Journal of Hepatology, Vol. 55, No. 4, 2011, p. 762 - 769.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway

AU - Lang, Tali

AU - Lo, Camden

AU - Skinner, Narelle

AU - Locarnini, Stephen

AU - Visvanathan, Kumar

AU - Mansell, Ashley

PY - 2011

Y1 - 2011

N2 - Viruses target innate immune pathways to evade host antiviral responses. Recent studies demonstrate a relationship between hepatitis B disease states and the host s innate immune response, although the mechanism of immunomodulation is unknown. In humans, the innate immune system recognizes pathogens via pattern recognition receptors such as the Toll-like receptors (TLR), initiating an anti-inflammatory responses. Previous studies have shown that both TLR expression and pro-inflammatory cytokine production is reduced in hepatitis B e antigen (hbeag)-positive patients compared to hbeag-negative patients following TLR stimulation. The aim of this study was to investigate interactions between TLR signaling pathways and the mature hbeag protein localized in the cytosol METHODS AND RESULTS: Our findings show that hbeag co-localizes with Toll/IL-1 receptor (TIR) -containing proteins TRAM, Mal and TLR2 at the sub-cellular level. Conversely, Hepatitis B core antigen did not co-localize with TIR proteins. Co-immunoprecipitation analysis further demonstrated hbeag interaction with TIR proteins Mal and TRAM, while a mutated form of hbeag ablated interaction with Mal and myd88. Importantly, hbeag was able to disrupt homotypic TIR:TIR interaction critical for TLR-mediated signalling. Finally, hbeag specifically suppressed TIR-mediated activation of the prototypic inflammatory transcription factors, NF-kappab and Interferon-beta promoter activity CONCLUSION: Our study provides the first molecular mechanism describing hbeag immunomodulation of innate immune signal transduction pathways via interaction and targeting of TLR-mediated signaling pathways. These finding suggest the mechanism as to how hbeag evades innate immune responses contributing to the pathogenesis of chronic hepatitis B infection and the establishment of viral persistence.

AB - Viruses target innate immune pathways to evade host antiviral responses. Recent studies demonstrate a relationship between hepatitis B disease states and the host s innate immune response, although the mechanism of immunomodulation is unknown. In humans, the innate immune system recognizes pathogens via pattern recognition receptors such as the Toll-like receptors (TLR), initiating an anti-inflammatory responses. Previous studies have shown that both TLR expression and pro-inflammatory cytokine production is reduced in hepatitis B e antigen (hbeag)-positive patients compared to hbeag-negative patients following TLR stimulation. The aim of this study was to investigate interactions between TLR signaling pathways and the mature hbeag protein localized in the cytosol METHODS AND RESULTS: Our findings show that hbeag co-localizes with Toll/IL-1 receptor (TIR) -containing proteins TRAM, Mal and TLR2 at the sub-cellular level. Conversely, Hepatitis B core antigen did not co-localize with TIR proteins. Co-immunoprecipitation analysis further demonstrated hbeag interaction with TIR proteins Mal and TRAM, while a mutated form of hbeag ablated interaction with Mal and myd88. Importantly, hbeag was able to disrupt homotypic TIR:TIR interaction critical for TLR-mediated signalling. Finally, hbeag specifically suppressed TIR-mediated activation of the prototypic inflammatory transcription factors, NF-kappab and Interferon-beta promoter activity CONCLUSION: Our study provides the first molecular mechanism describing hbeag immunomodulation of innate immune signal transduction pathways via interaction and targeting of TLR-mediated signaling pathways. These finding suggest the mechanism as to how hbeag evades innate immune responses contributing to the pathogenesis of chronic hepatitis B infection and the establishment of viral persistence.

UR - http://www.ncbi.nlm.nih.gov/pubmed/21334391

U2 - 10.1016/j.jhep.2010.12.042

DO - 10.1016/j.jhep.2010.12.042

M3 - Article

VL - 55

SP - 762

EP - 769

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

IS - 4

ER -