Immune system-independent mechanisms of hepatic pathogenesis and carcinogenesis in Schistosoma mansoni/hepatitis B virus co-infection

在血吸虫病流行地区，慢性血吸虫病和乙肝病毒合并感染的发生率不成比例。以前感染过曼氏沙门氏菌被怀疑是感染乙肝病毒(乙肝病毒)和丙型肝炎病毒(丙型肝炎病毒)的易感因素。乙肝病毒和曼氏葡萄球菌的混合感染也加速了肝病的进展，通过增加肝硬变和肝癌的发病率增加了死亡率。肝细胞应激、肝纤维化和合并感染时的癌变等内源性损害宿主实质的分子机制迄今尚未得到解决，尽管它们很可能在疾病进展中发挥作用，正如我们在乙肝和血吸虫病诱导的肝脏发病机制方面的初步工作所表明的那样。基于曼氏葡萄球菌/乙肝病毒混合感染的临床研究和我们的初步工作，我们旨在分析免疫系统无关的机制如何参与肝脏的发病和肿瘤的发生。由于现有的临床数据表明，先前感染曼氏葡萄球菌可以促进肝细胞癌的发生，这一点也应该得到重视。在目前的项目中，我们的目标是在乙肝模型中表征同时感染和先前感染曼氏葡萄球菌的病理机制。假设1：曼氏血吸虫诱导的代谢应激和乙肝病毒表面蛋白诱导的肝细胞内质应激协同放大导致的肝实质损伤和癌变。在小鼠乙肝病毒模型中，曼氏沙门氏菌混合感染组分中肝实质损伤的分子生物学原理有待确定。在功能得失的实验中，分析了发病机制以及诊断和治疗的选择。假设2：在乙肝小鼠模型中，治疗成功的曼氏葡萄球菌感染会增加肝细胞癌的发生率和侵袭性。在血吸虫病流行的地区，每年有超过2亿人接受吡喹酮的预防性治疗，这种药物可以杀死虫子，但不会杀死寄生虫的卵。在乙肝小鼠模型中，对成功治疗曼氏血吸虫混合感染后持续寄生虫卵造成的肝脏损害进行了分析。在功能得失实验中，分析了发病机制的关系以及诊断和治疗方案。来自两个TPS模型的结果将使用原代人类肝细胞和人类参考样本进行验证。

Chronic stages of schistosomiasis and HBV occur disproportionately often as co-infections in endemic areas. A previous infection with S. mansoni is suspected to predispose for infections with hepatitis B virus (HBV) and hepatitis C virus (HCV). Co-infections of HBV and S. mansoni also accelerate liver disease progression, increase mortality through an enhanced incidence of liver cirrhosis and HCC. Molecular mechanisms of endogenous damage to the host parenchyma by e.g. hepatocellular stress, fibrosis, and carcinogenesis during co-infection have not been addressed so far, although they very likely play a role in disease progression, as our preliminary work on HBV- and schistosomiasis-induced liver pathogenesis suggests. Based on clinical studies on S. mansoni/HBV co-infection and our preliminary work, we aim to analyze how immune system-independent mechanisms are involved in hepatic pathogenesis and carcinogenesis. Since the available clinical data suggest that a previous infection with S. mansoni can promote hepatocellular carcinogenesis, this point should also be addressed. With the present project, we aim to characterize pathological mechanisms of a concurrent and previous infection of S. mansoni in HBV models. Hypothesis 1: S. mansoni-induced metabolic stress and HBV surface protein-induced endoplasmic stress in hepatocytes synergistically amplify resulting liver parenchyma damage and carcinogenesis. In the murine HBV model, molecular-biological principles of hepatic parenchyma damage in components of a S. mansoni co-infection are to be determined. Mechanistic relationships of the pathogenesis as well as diagnostic and therapeutic options are analyzed in gain-and-loss-of-function experiments. Hypothesis 2: A successfully treated previous infection with S. mansoni increases the incidence and aggressiveness of hepatocellular carcinogenesis in the HBV mouse model. In regions where schistosomiasis is endemic, more than 200 million people are treated prophylactically with praziquantel each year, which kills the worms but not the eggs of the parasite. In the HBV mouse model, liver damage caused by persistent parasite eggs after a successfully treated S. mansoni co-infection is to be analyzed. In gain-and-loss-of-function experiments, mechanistic relationships of the pathogenesis as well as diagnostic and therapeutic options are analyzed. The results from the models of both TPs are to be validated using primary human hepatocytes and human reference samples.