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

详细信息    查看全文

• 作者：Tali Lang¹ ; Camden Lo² ; Narelle Skinner³ ; Stephen Locarnini⁴ ; Kumar Visvanathan³ ; ^&dagger ; ; Ashley Mansell¹ ; ^&dagger ; ; ^{Ashley.Mansell@monash.edu}
• 关键词：HBeAg ; hepatitis B e antigen ; HBV ; hepatitis B virus ; CHB ; chronic hepatitis B ; HBcAg ; hepatitis B core antigen ; NF-¦ÊB ; nuclear factor kappa B ; TNF-¦Á ; tumor necrosis factor alpha ; TLR ; Toll-like receptor ; TIR ; Toll/IL-1 receptor ; IL ; interleukin ; IFN ; i
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：October, 2011
• 年：2011
• 卷：55
• 期：4
• 页码：762-769
• 全文大小：1K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

Background & Aims

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 anti-inflammatory responses. TLR expression and pro-inflammatory cytokine production is reduced in hepatitis B e antigen (HBeAg)-positive 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

The ability of HBeAg to inhibit TLR signaling and association with TLR adapters was evaluated by immunoprecipitation, immunostaining, and reporter studies.

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, which was not observed for Hepatitis B core antigen. Co-immunoprecipitation analysis demonstrated HBeAg interacted with TIR proteins Mal and TRAM, while a mutated HBeAg ablated interaction between Mal and MyD88. Importantly, HBeAg also disrupted homotypic TIR:TIR interaction critical for TLR-mediated signaling. Finally, HBeAg suppressed TIR-mediated activation of the inflammatory transcription factors, NF-¦ÊB and Interferon-¦Â promoter activity.

Conclusions

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.