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

项目摘要 肠道微生物群和宿主免疫系统已经共同进化了数千年。但现代 社会条件扰乱了这种共同进化，这与免疫介导的免疫系统的急剧上升相吻合。 疾病细菌移位穿过肠屏障进入肠外器官如肝脏， 有严重的病理后果。肠道细菌，鸡肠球菌， 可引发自身反应性和慢性炎症，导致自身免疫性肝病， 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E。尤其是鸡 能够穿过上皮移位并在正常无菌的组织如肝脏中持续存在。理解 使E.鸡蛔虫穿过肠屏障可能导致发展 新的治疗策略，以减轻自身免疫性肝病的开始或进展。我 初步结果表明，E.鸡胚在消化后迅速获得在肠内移位的能力， 无菌小鼠的单定殖。我推测E.鸡肝 当它获得在肠道微生物群背景下规避宿主免疫反应的能力时发生。 在这里，我建议：1）测试的假设，E。鸡胚通过逃避 免疫监视; 2）确定特定的肠道菌群是否能阻碍E.鸡胚易位 通过免疫启动。在第一个目标中，我将阐明如何E。鸡胚能逃避宿主免疫 反应，使用新开发的技术来分析E.鸡球虫对宿主 胞外蛋白质在第二个目标中，我将进行E.鸡在五个方面 独特的健康人类肠道微生物，并确定居民肠道微生物介导的宿主的变异性 对E.鸡胚易位这些研究将提供深入了解 肠道细菌移位穿过肠屏障并诱导肝硬化的基本机制 自身免疫因此，它们可以阐明用于治疗以下疾病的新治疗策略的潜在靶点： 慢性自身免疫性肝病具有重大的社会，情感和经济成本， 目前没有治愈方法。

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.