Elucidating the pathological translocation mechanism(s) of a commensal bacterium in autoimmune liver disease

项目总结 数千年来，肠道微生物群和宿主免疫系统一直是共同进化的。然而，现代的 社会条件扰乱了这种共同进化，这与免疫调节的急剧上升不谋而合。 疾病。细菌跨过肠道屏障进入肠道外器官，如肝脏 会造成严重的病理后果。共生细菌鸡肠球菌的易位， 可引发自身反应性和慢性炎症，导致自身免疫性肝病，如 自身免疫性肝炎和原发性硬化性胆管炎。然而，目前还不清楚鸡冠埃希氏菌是如何 能够通过上皮转移，并在正常情况下无菌的组织中持续存在，如肝脏。理解 鸡冠埃希氏菌通过肠道屏障的确切机制(S)可能导致 研究新的治疗策略，以减轻自身免疫性肝病的发病或进展。我的 初步结果表明，鸡嗜血杆菌在感染后迅速获得在肠道内移位的能力。 无菌小鼠的单系繁殖。我推测鸡冠埃希菌自发移位到肝脏 当它在肠道微生物区系背景中获得绕过宿主免疫反应的能力时发生。 在这里，我建议：1)检验假设，即鸡冠埃希氏菌通过逃避 免疫监测；以及，2)确定特定的肠道共生体是否可以阻止鸡肠杆菌的易位 通过免疫启动。在第一个目标中，我将阐明鸡肠杆菌是如何逃避宿主免疫的。 用一种新开发的技术描述鸡冠埃希氏菌与宿主的差异结合 胞外蛋白。在第二个目标中，我将在五个背景下进行鸡冠埃希氏菌的体内定植 独特的健康人体肠道微生物区系，并确定驻留肠道微生物区系介导的宿主的变异性 鸡嗜血杆菌易位的免疫防御。这些研究将为我们提供对 共生细菌跨过肠道屏障并诱导肝脏的基本机制 自身免疫力。因此，它们可能为新的治疗策略提供潜在的靶点。 慢性自身免疫性肝病，有重大的社会、情感和经济代价，对此有 目前还没有治愈的方法。

Project summary The resident gut microbiota and the host immune system have co-evolved for millennia. However, modern societal conditions have disturbed this co-evolution and this has coincided with a steep rise in immune-mediated diseases. Bacterial translocation across the intestinal barrier and into extraintestinal organs such as the liver can have major pathological consequences. Translocation of the commensal bacterium, Enterococcus gallinarum, can trigger autoreactivity and chronic inflammation, contributing to autoimmune liver diseases such as autoimmune hepatitis and primary sclerosing cholangitis. However, it is unknown how E. gallinarum in particular is able to translocate across the epithelium and persist in normally sterile tissues such as the liver. Understanding the exact mechanism(s) that enable E. gallinarum to cross the intestinal barrier could lead to the development of novel therapeutic strategies to mitigate the initiation or progression of autoimmune liver disease. My preliminary results suggest that E. gallinarum rapidly acquires the ability to translocate within the intestine after monocolonization of germ-free mice. I hypothesize that spontaneous translocation of E. gallinarum to the liver occurs when it acquires the ability to circumvent the host immune response in a gut microbiota background. Here, I propose to: 1) test the hypothesis that E. gallinarum attains the capability to translocate by evading immune surveillance; and, 2) determine whether specific gut commensals can hinder E. gallinarum translocation via immunological priming. In the first aim, I will elucidate how E. gallinarum is able to evade host immune response using a newly developed technology to profile differential binding of E. gallinarum isolates to host extracellular proteins. In the second aim, I will perform in vivo colonization of E. gallinarum in the context of five unique healthy human gut microbiotas, and determine the variability in resident gut microbiota-mediated host immunological defense against E. gallinarum translocation. These studies will provide insight into the fundamental mechanisms by which commensal bacteria translocate across the intestinal barrier and induce liver autoimmunity. Thus, they may illuminate potential targets for novel therapeutic strategies for the treatment of chronic autoimmune liver diseases that have major social, emotional, and financial costs and for which there are currently no cures.