Impact of parenchymal and nonparenchymal liver cells on Hepatitis B virus infection - Virus host interactions determine immunopathology and chronicity

由乙肝病毒感染引起的慢性病毒性肝炎是最常见的肝脏相关发病率和死亡率的原因之一。近年来发现，不仅获得性免疫系统参与了该病的发病，先天免疫系统也参与了该病的发病。病原体识别受体在先天性免疫中起核心作用，最近被认为影响慢性病毒性肝炎。然而，在进化过程中，乙肝病毒已经进化出逃避策略，以破坏肝脏的天然免疫系统，这对于理解导致乙肝病毒感染慢性化的机制具有重要意义。之前已经在体外研究了通过单一病毒蛋白或感染复制模型转基因的肿瘤细胞系中乙肝病毒的免疫逃逸。在体内，在感染了乙肝病毒的人源化小鼠和慢性感染患者中也发现了免疫逃避的现象。乙肝病毒表面抗原(HBs Ag)是一种耐受原，被认为是免疫逃避事件的主导者。这项建议的目的是详细描述作为慢性乙肝病毒感染模型的乙肝转基因小鼠的肝内免疫控制，重点关注以主要靶细胞(肝细胞)和免疫活性的非实质肝细胞为代表的肝环境与乙肝病毒之间的分子相互作用。关键的问题是，乙肝表面抗原如何影响这些细胞的免疫功能，从而控制肝脏的先天性和获得性免疫反应，将使用不同的乙肝转基因小鼠品系来解决，这些品系的肝脏表型不同。缺乏乙肝表面抗原的菌株表现出抗病毒信号，而只表达乙肝表面抗原的Alb/HBs动物则表现出炎症过程。有趣的是，通过杂交获得的乙肝表面抗原回收株显示出正常的肝脏表型，表明发生了免疫逃避事件。这些模型之间的比较将使我们能够得出关于乙肝表面抗原依赖和非乙肝表面抗原免疫逃避事件的结论，这些事件将进行机械分析。这项工作的一个前景是识别来自不同肝细胞类型的特定的乙肝病毒诱导的血清标志物，从而能够单独评估慢性乙肝病毒携带者的免疫病理。这些预期的发现将增加对慢性感染患者中乙肝病毒如何持续存在的了解。这些发现可能会导致个性化治疗策略的优化。

Chronic viral hepatitis caused by Hepatitis B virus (HBV) infection is among the most frequent causes for liver related morbidity and mortality. In recent years, it has become clear that not only the adaptive but also the innate immune system is involved in the pathogenesis of this infection. Pathogen recognition receptors, playing a central role in innate immunity, have recently been recognized to affect chronic viral hepatitis. However, HBV has evolutionarily evolved evading strategies to subvert the innate immune system of the liver, which is of relevance for understanding the mechanisms leading to chronicity of HBV infection. Immune evasion of HBV has been previously investigated in tumour cell lines transgenic for single viral proteins or infectious replication models, in vitro. Observation of immune evasion has also been found in HBV-infected humanized mice and chronically infected patients, in vivo. The HBV surface antigen (HBsAg) is a tolerogen that is supposed to dominate the immune evasion events. Aim of this proposal is the detailed description of intrahepatic immune control in HBV-transgenic mice, as a model for chronic HBV infection, focusing on molecular interactions between HBV and the hepatic environment represented by the major target cells (hepatocytes) and the immuno active non-parenchymal liver cells. The crucial question, how HBsAg affect the immunological function of these cells, and thereby control hepatic innate and adaptive immune responses, will be addressed using diverse HBV transgenic mouse strains, which differ in their hepatic phenotype. An HBsAg-deficient strain exhibit antiviral signaling, whereas Alb/HBs animals, that solely express HBsAg, show an inflammatory process. Interestingly, the HBsAg recovered strain, obtained by crossbreeding show a normal liver phenotype, indicating events of immune evasion. Comparisons between these models will allow drawing conclusions on HBsAg-dependent and HBsAg-independent immune evasion events, which will be mechanistically analyzed. One perspective of this work is the identification of specific HBV-induced serum markers that originate from the diverse liver cell types, allowing to individually rate the immunopathology of chronic HBV carriers. The expected findings will increase the knowledge on how HBV persists in chronically infected patients. These findings might lead to optimization of personalized treatment strategies.