The interaction of Hepatitis B virus infection and Schistosomiasis in chronic pathogen-induced liver inflammation

乙型肝炎病毒（HBV）感染的主要并发症之一是急性感染后发展为慢性肝炎，慢性乙型肝炎患者发展为肝硬化和肝细胞癌（HCC）的风险很高。有趣的是，在发展中国家，慢性乙型肝炎和肝细胞癌的发病率更高，在这些国家，几种蠕虫（蠕虫）的共同感染很常见，如人类病原体曼氏血吸虫（血吸虫的病原体）。蠕虫引起慢性感染，为了建立这些感染，它们已经发展出强大的免疫调节甚至抑制能力。在合并感染期间，这些因素可能通过损害抗病毒免疫反应和肝脏疾病进展而导致HBV持续存在。然而，血吸虫诱导的免疫反应是非常动态的，范围从急性，炎症到慢性，抗炎（Th2）和免疫调节阶段，其中抑制细胞如调节性T细胞（Treg）发挥重要作用。我们认为，这种情况，以及曼森氏杆菌也引起肝脏疾病的事实，可能导致急性和慢性HBV感染的不同结果。因此，本提案的主要目标是详细研究在已存在的曼森尼感染期间诱导的急性和慢性免疫阶段对急性HBV感染结果的影响，以及相关的，随后的曼森尼感染对已存在的慢性HBV感染的影响，特别关注肝脏内的细胞过程，因为肝脏主要受到这两种病原体的影响。研究结果将加深我们对为什么第三世界（蠕虫流行）国家的HBV慢性率比工业化国家高得多的理解。在未来，这可能会对全球范围内的乙型肝炎治疗和疫苗接种工作产生直接影响，目前这些工作忽视了寄生虫合并感染的作用。

One of the main complications of hepatitis B virus (HBV) infection is the development of chronic hepatitis after an acute infection, and patients with chronic hepatitis B are at high risk to develop liver cirrhosis and hepatocellular carcinoma (HCC). Interestingly, chronic hepatitis B and also HCC develop at a higher frequency in developing countries in which co-infections with several helminth (worm) species such as the human pathogen Schistosoma mansoni (the causative agent for bilharzia) are common. Helminths cause chronic infections and to establish these they have developed strong immuneregulatory and even suppressive capacities. During co-infection these may contribute to HBV persistence by compromising anti-viral immune responses, and to liver disease progression. Schistosome-induced immune responses, however, are very dynamic and range from an acute, inflammatory to a chronic, anti-inflammatory (Th2) and immuneregulatory phase where suppressor cells like regulatory T cells (Treg) play an important role. We believe that this circumstance, as well as the fact that S. mansoni also causes liver disease, could lead to very different outcomes of concomitant acute and chronic HBV infection. Therefore, the main objectives within this proposal are to investigate in detail the impact of the acute and chronic immune phases induced during preexisting S. mansoni infection on the outcome of acute HBV infection and in correlation, the impact of subsequent S. mansoni infection on preexisting, chronic HBV infection with a special focus on the cellular processes within the liver since this organ is mainly affected by both pathogens. The results will deepen our understanding why HBV chronicity rates are much higher in third world (helminth-endemic) countries compared to industrialized ones. In the future, this may have direct impact on world-wide treatment and vaccination efforts for hepatitis B, which currently disregard the role of helminth co-infections.