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

描述（由申请人提供）：动物的肠道被大量的共生微生物定植，这些微生物有助于许多宿主的生理过程。肠道微生物群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定植和入侵。然而，微生物群和宿主免疫系统之间的相互作用，介导对肠道病原体的保护，仍然知之甚少。此外，肠道病原体用来克服微生物群存在的机制仍然知之甚少。我们发现共生菌群对于消除鼠柠檬酸杆菌至关重要，鼠柠檬酸杆菌是一种肠道小鼠病原体，可以模拟人类感染腹泻性肠出血性大肠杆菌（EHEC）和肠致病性大肠杆菌（EPEC）。肠出血性大肠杆菌和肠出血性大肠杆菌是世界范围内水样腹泻和死亡的重要原因。这些革兰氏阴性细菌是通过食物和水传播的非侵入性病原体，它们通过在肠上皮上诱导特征性的附着和消退（A/E）病变附着并定植在肠道上，导致人类短暂性肠炎或结肠炎。EPEC和EPEC及相关病原体的基因组包含肠细胞消失（LEE）的位点，这对细菌定植和引起病理的能力至关重要。LEE毒力因子由转录因子Ler控制，该转录因子作为LEE毒力基因的全局调节因子。我们计划在本提案中使用啮齿柠檬酸杆菌模型来检验我们的初步结果提出的几个假设。本研究的目的是为了更好地了解病原体、宿主免疫系统和本地微生物群之间的相互作用，这些相互作用对控制肠道病原体的定植和根除至关重要。此外，我们建议开发新的治疗策略来治疗C.啮齿动物诱导的结肠炎，基于本地微生物群的能力，以降低ler介导的毒力来战胜病原体。鉴于A/E病原体是人类死亡和发病的主要原因，该提案预计将在医学领域产生重大而广泛的影响

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