乙型肝炎病毒（HBV）感染重症化过程中免疫耐受打破，炎症级联放大，激活机制未明。申请人及所在课题组在国际上首次发现重症化的极端表型暴发性乙型肝炎患者存在显著的TLR2通路罕见缺陷，且TIR结构区突变多见，体内体外实验证实TLR2缺陷与炎症相关。已知部分HBcrAg能与胞内TIR结构共定位，由此假设TLR2通路TIR候选位点在HBV感染中能够传递异常炎症信号，机制可能涉及HBcrAg。研究将围绕TIR突变，观察其对TLR2-NF-κB炎症通路的影响；并观察加入HBcrAg后对上述炎症通路的影响；通过HTRF等蛋白互作技术检测HBcrAg与TIR突变分子结合能力；在自主建立的急、慢性TLR2缺陷小鼠感染模型中验证TIR候选突变对血清、肝组织炎症及免疫细胞亚群激活的影响。研究结果将有助于理解HBV炎症调控机制，为控制重症化、提供药筛靶位提供重要依据。

Severe exacerbation developed during hepatitis B virus (HBV) infection breaks the immune tolerance and leads to cascading events of inflammatory responses, the cause of which remains elusive. We previously found rare TLR2 pathway impairment in sporadic HBV related fulminant hepatitis cases. Several rare mutations identified lied within TIR domain, with evidences associating TLR2 deficiency with inflammation both in vitro and in vivo. Together with the fact that some HBcrAgs were shown to be able to co-localize intracellularly with TIR domain, we hypothesize these TIR sites within TLR2 pathway play important proinflammatory role during HBV infection, HBcrAg probably involved. The TIR candidate mutations' impact on the magnitude of NF-κB activation and inflammatory cytokines expressions, upon ligands stimulation with or without the presence of HBcrAgs, will be evaluated. Protein-protein interaction studies, mainly by HTRF technique, will be used to test the binding capacities between TIR mutants and HBcrAgs. The chosen TIR mutants’ effect on peripheral, intrahepatic inflammation and activations of immune cells subtypes both in the context of acute and chronic settings will be tested in TLR2 knock-out mice. The results will further our understanding toward HBV related severe exacerbation, while the data will provide valuable insights to the screening of molecules with immune modulating potential for the treatment of HBV related severe exacerbations.