Bacterial Virulence and the Microbiota in Eradication of Enteropathogenic E. Coli

描述(申请人提供)：动物的肠道被大量的共生微生物定植，这些微生物对宿主的许多生理过程都有贡献。肠道微生物区系的一个重要作用是保护宿主免受经常进入肠道的病原体的侵袭和侵袭。然而，微生物区系和宿主免疫系统之间的相互作用调节对肠道病原体的保护作用仍然知之甚少。此外，肠道病原体用来克服微生物区系存在的机制仍然知之甚少。我们发现，共生微生物群对于消除轮状柠檬酸杆菌至关重要。轮状柠檬酸杆菌是一种小鼠肠道病原体，可模拟人类感染致泻性肠出血性(EHEC)和致病性(EPEC)大肠杆菌。EHEC和EPEC是全世界水样腹泻和死亡的重要原因。这些革兰氏阴性菌是食物和水传播的非侵袭性病原体，通过在肠道上皮诱导特征性的附着和消失(A/E)病变而附着和定植于肠道，导致人类一过性肠炎或结肠炎。EPEC和EPEC及其相关病原体的基因组中含有肠上皮细胞消亡基因(Lee)，该基因对细菌的定植和致病能力至关重要。李氏毒力因子由LER控制，LER是一种转录因子，充当李氏毒力基因的Globa调节器。在这项提案中，我们计划使用轮状柠檬酸杆菌模型来检验我们的初步结果提出的几个假设。这项建议的目标是更好地了解病原体、宿主免疫系统和本土微生物群之间的相互作用，这些微生物群在控制肠道病原体的定植和根除方面至关重要。此外，我们建议开发新的治疗策略来治疗轮齿菌引起的结肠炎，这是基于本土微生物区系以降低LER介导的毒力击败病原体的能力。鉴于A/E病原体是人类死亡和发病的主要原因，这项提议预计将在医疗领域产生重大和广泛的影响

DESCRIPTION (provided by applicant): The intestine of animals is colonized by a large number of commensal microorganisms that contribute to many host physiological processes. An important role of the intestinal microbiota is to protect the host against colonization and invasio by pathogens that often enter the intestinal tract. However, the interaction between the microbiota and the host immune system that mediates protection against enteric pathogens remains poorly understood. Furthermore, the mechanisms that enteric pathogens employ to overcome the presence of the microbiota remain poorly understood. We find that the commensal microbiota is critical for the elimination of Citrobacter rodentium, an enteric mouse pathogen that models human infection by diarrheagenic enterohemorrhagic (EHEC) and enteropathogenic (EPEC) Escherichia coli. EHEC and EPEC are important causes of watery diarrhea and mortality worldwide. These Gram-negative bacteria are food- and waterborne non-invasive pathogens which attach to and colonize the intestinal tract by inducing characteristic attaching- and-effacing (A/E) lesions on the intestinal epithelium, leading to transient enteritis r colitis in humans. The genome of EPEC and EPEC and related pathogens harbor the locus for enterocyte effacement (LEE) which is critical for bacterial colonization and the ability to cause pathology. LEE virulence factors are controlled by Ler, a transcription factor that acts as a globa regulator of LEE virulence genes. We plan in this proposal to use the Citrobacter rodentium model to test several hypotheses raised by our Preliminary Results. The goal of this proposal is to gain a better understanding of the interactions among the pathogen, the host immune system and the indigenous microbiota that are critical in controlling the colonization and eradication of enteric pathogens. In addition, we propose to develop novel therapeutic strategies to treat C. rodentium-induced colitis based on the ability of the indigenous microbiota to outcompete the pathogen with reduced Ler-mediated virulence. Given that A/E pathogens are a major cause of death and morbidity in human populations, this proposal is expected to have a significant and broad impact in the medical field