O031 : TG1050, a novel immunotherapeutic to treat chronic hepatitis B, can control HBsAg and provoke HBsAg seroconversion in HBV-persistent mouse models
التفاصيل البيبلوغرافية
العنوان:
O031 : TG1050, a novel immunotherapeutic to treat chronic hepatitis B, can control HBsAg and provoke HBsAg seroconversion in HBV-persistent mouse models
Methods: We infected mice with a hepatotropic virus and challenged these mice by injecting TNF. Using knockout mice, as well as biochemical and multiparametric histological methods we analyzed the influence of different pattern recognition receptors. Additionally, we isolated mitochondria from virus-infected mice and performed metabolomic investigations to analyze the role of mitochondria in virus recognition as well as their role in apoptosis execution. Results: We demonstrate that viral infection in hepatocytes is recognized even in the absence of classical pattern recognition receptor signaling. Rather, viral infection of hepatocytes modulates metabolic processes, leads to increased levels of the pro-apoptotic BCL-2 family members Bax and Bad that cause damage to mitochondria. This leads to a downregulation of the anti-apoptotic protein XIAP (X-chromosome linked inhibiting of apoptosis protein). Downregulation of XIAP facilitates TNF-induced activation of the initiator caspase 8 that together with increased mitochondrial sensitivity to activated caspase 8 is responsible for TNF-induced cell death in virus-infected hepatocytes. Conclusions: We have identified a novel immune-sensing mechanisms in virus-infected hepatocytes that links effector molecules generated by virus-specific T cells to cell-autonomous induction of death selectively in virus-infected hepatocytes.
