The Role of FimH in ExPEC Translocation

项目摘要 肠道细菌从肠道到血液和其他器官的运动被称为 易位，这是一个在20世纪60年代临床上认识到的概念， 80年代易位是危及生命的菌血症发展的主要前兆， 脓毒症，免疫系统受损是主要风险因素。的重要原因 肠源性脓毒症是ExPEC，临床上最常见的革兰氏阴性菌 从菌血症病人身上提取的病原体ExPEC通常具有多重耐药性，有证据表明 这些菌株可能是胃肠道的慢性定植者。没有疫苗。机制 ExPEC从肠道转移出来的方式尚未确定， 这一进程所需的因素仍然未知。本供资期建议确定 菌毛尖端粘附素FimH在易位中的重要性。 本文提供的初步数据表明，FimH是ExPEC临床菌株结合所需的， 侵入并通过转化的肠细胞系。假设FimH是必要的 对于人类宿主中的易位，我们在这里测试FimH通过 人肠上皮细胞和白细胞减少症小鼠模型易位。我们还使用 这些模型系统，我们的实验室开发，以确定分子的要求， FimH介导的通过肠上皮细胞的易位，FimH在全球的重要性， ExPEC的循环谱系，以及不同的FimH等位基因是否决定易位的效率。 这项工作将确定FimH是否是预防高危患者肠源性脓毒症的可行靶点。 患者

Project Summary The movement of enteric bacteria from the intestine to the blood and other organs is called translocation, a concept recognized clinically in the 1960s and defined experimentally in the 1980s. Translocation is a major precursor to the development of life-threatening bacteremia and sepsis, with a compromised immune system being a dominant risk factor. A significant cause of gut-derived sepsis is ExPEC, which clinically is the most frequently isolated Gram-negative pathogen from bacteremic patients. ExPEC is often multi-drug resistant, and there is evidence that such strains may be chronic colonizers of the GI tract. There is no vaccine. The mechanism by which ExPEC translocates out of the intestine has not been determined, and the bacterial factors needed for this process remain unknown. This funding period proposes to determine the importance of the pilus tip adhesin FimH in translocation. Preliminary data presented here suggests FimH is required for clinical strains of ExPEC to bind, invade, and pass through a transformed intestinal cell line. Hypothesizing that FimH is necessary for translocation in human hosts, we test here the requirements of FimH for passage through human intestinal enteroids and translocation in a murine model of leukopenia. In addition, we use these model systems, which our laboratory developed, to determine the molecular requirements of FimH-mediated translocation through enterocytes, the importance of FimH in globally circulating lineages of ExPEC, and if distinct FimH alleles dictate the efficiency of translocation. This work will determine if FimH is a viable target for preventing gut-derived sepsis in high-risk patients.