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

由乙型肝炎病毒（HBV）感染引起的慢性病毒性肝炎是肝脏相关发病和死亡的最常见原因之一。近年来，人们已经清楚，不仅是适应性免疫系统，而且先天免疫系统也参与了这种感染的发病机制。病原体识别受体，在先天免疫中起着核心作用，最近被认为影响慢性病毒性肝炎。然而，HBV已经进化出了规避策略来破坏肝脏的先天免疫系统，这与理解导致HBV感染的慢性机制有关。HBV的免疫逃避已经在肿瘤细胞系中进行了研究，这些肿瘤细胞系被转基因为单一病毒蛋白或感染复制模型。在hbv感染的人源化小鼠和慢性感染患者体内也发现了免疫逃避现象。HBV表面抗原（HBsAg）是一种被认为主导免疫逃避事件的耐受性原。本文的目的是详细描述HBV转基因小鼠的肝内免疫控制，作为慢性HBV感染的模型，重点关注HBV与以主要靶细胞（肝细胞）和免疫活性非实质肝细胞为代表的肝脏环境的分子相互作用。关键的问题是，HBsAg如何影响这些细胞的免疫功能，从而控制肝脏先天和适应性免疫反应，将通过不同的HBV转基因小鼠株来解决，这些小鼠株在肝脏表型上有所不同。缺乏HBsAg的菌株表现出抗病毒信号，而仅表达HBsAg的Alb/HBs动物则表现出炎症过程。有趣的是，通过杂交获得的HBsAg恢复株显示出正常的肝脏表型，表明免疫逃避事件。这些模型之间的比较将有助于得出hbsag依赖性和hbsag非依赖性免疫逃避事件的结论，并将对其进行机制分析。这项工作的一个观点是鉴定来自不同肝细胞类型的特异性HBV诱导血清标志物，允许单独评估慢性HBV携带者的免疫病理。预期的发现将增加对慢性感染患者中HBV如何持续存在的认识。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.