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

慢性期血吸虫病和HBV在流行地区不成比例地经常作为合并感染发生。既往感染S.曼氏菌被怀疑易感染B型肝炎病毒（HBV）和丙型肝炎病毒（HCV）。HBV和S. mansoni还通过增加肝硬化和HCC的发病率加速肝病进展，增加死亡率。到目前为止，通过例如肝细胞应激、纤维化和共感染期间的致癌作用对宿主实质的内源性损伤的分子机制尚未得到解决，尽管它们很可能在疾病进展中发挥作用，正如我们对HBV和疟原虫诱导的肝脏发病机制的初步研究所表明的那样。根据对S. mansoni/HBV共感染和我们的初步工作，我们的目的是分析免疫系统无关的机制是如何参与肝脏发病机制和癌变。由于现有的临床资料表明，以前感染的S。mansoni可以促进肝细胞癌的发生，这一点也应该得到重视。本研究的目的是探讨同时感染和既往感染沙门氏菌的病理机制。在HBV模型中的mansoni。假设1：S。在肝细胞中，曼森氏诱导的代谢应激和HBV表面蛋白诱导的内质应激协同放大了所产生的肝实质损伤和致癌作用。在小鼠HBV模型中，S。要确定是否存在曼氏菌合并感染。在功能获得和丧失实验中分析了发病机制以及诊断和治疗选择的机制关系。假设2：成功治疗了先前的S. mansoni增加HBV小鼠模型中肝细胞癌发生的发生率和侵袭性。在血吸虫病流行的地区，每年有2亿多人接受吡喹酮治疗，吡喹酮可以杀死蠕虫，但不能杀死寄生虫的卵。在HBV小鼠模型中，成功治疗S。将分析曼氏菌合并感染。在功能获得和丧失实验中，分析了发病机制以及诊断和治疗选择的机制关系。使用原代人肝细胞和人参比样品验证两种TP模型的结果。

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.