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

描述（由申请人提供）：动物肠道内定植有大量肠道微生物，这些微生物有助于许多宿主生理过程。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，微生物群与宿主免疫系统之间介导对肠道病原体的保护的相互作用仍然知之甚少。此外，肠道病原体用于克服微生物群存在的机制仍然知之甚少。我们发现，肠道微生物群是至关重要的，以消除柠檬酸杆菌啮齿类，肠道小鼠病原体，模型人类感染的致肠出血性大肠杆菌（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引起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入性病原体，其通过在肠上皮上诱导特征性附着和消退（A/E）病变而附着并定殖于肠道，导致人类的短暂性肠炎或结肠炎。EPEC和EPEC以及相关病原体的基因组具有肠上皮细胞消失（LEE）的基因座，其对于细菌定殖和引起病理的能力是关键的。LEE毒力因子由Ler控制，Ler是一种转录因子，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类柠檬酸杆菌模型来测试我们的初步结果提出的几个假设。该提案的目标是更好地了解病原体、宿主免疫系统和土著微生物群之间的相互作用，这些相互作用对于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的基础上的能力，土著微生物群的竞争力，以降低Ler介导的毒力的病原体。鉴于A/E病原体是人类死亡和发病的主要原因，预计该提案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