Pathogen of Enterotoxigenic Bacteriodes Fragilis Infect

描述（由申请方提供）：脆弱拟杆菌是主要的 厌氧菌血症和腹腔内脓肿的原因。过去15 多年来，越来越多的数据表明，B的毒素分泌菌株。fragilis（英语：Fragilis） 肠促炎性B。fragilis或ETBF）作为大肠杆菌病的病原体 折磨着年幼的孩子和成年人。迄今为止，关于ETBF的可用人体数据 感染仅限于评估流行病学关联的研究 ETBF菌株腹泻，最近，炎症性肠病 和血液感染。然而，与以下疾病相关的临床综合征 肠ETBF感染是不明确的，这些感染的影响 对肠道结构和病理生理学的影响。关键 迄今为止鉴定的ETBF菌株的毒力因子是一种分泌的热不稳定的， 约20 kD金属蛋白酶毒素（B. fragilis毒素或BFT）。纯化的BFT和/或 感染ETBF刺激分泌，使肠上皮变圆 细胞与细胞接触的破坏和炎症， 小肠和结肠。类似的观察也在以下情况中出现： 在体外用BFT处理肠上皮细胞模型。在这些活 在体外模型中，我们的数据显示肠上皮细胞单层 抵抗，氯化物分泌，抑制Na+吸收， 促炎趋化因子白细胞介素-8所有这些数据都是一致的 假设ETBF和BFT是结肠炎的病原体 疾病为了开始填补我们对ETBF疾病认识的空白， 这项建议的具体目标是：1）深入研究 ETBF感染;和2）研究ETBF感染的发病机制， 特别关注它们对肠道结构和功能的影响。ETBF 将在儿童和成人的粪便中识别， 国际腹泻病研究中心腹泻医院 孟加拉国，ETBF感染先前已被证明是显著的 与牙周病有关。临床数据，急性期和恢复期血清 样本，粪便研究，以评估炎症介质的证据， 将获得结肠活组织检查并进行相关性分析，以确定流行病学， 感染的病理生理学。我们假设ETBF是一种 未被认识到的肠道病原体占以前 未确诊的儿童和成人炎症性肠道感染。

DESCRIPTION (provided by the applicant): Bacteroides fragilis are the leading causes of anaerobic bacteremia and intra-abdominal abscesses. Over the past 15 years, increasing data implicate toxin-secreting strains of B. fragilis (termed enterotoxigenic B. fragilis or ETBF) as causative agents in diarrheal disease afflicting young children and adults. To date, the available human data on ETBF infection has been limited to studies assessing the epidemiological association of ETBF strains with diarrhea and, more recently, inflammatory bowel disease and bloodstream infections. However, the clinical syndrome(s) associated with intestinal ETBF infections are ill-defined and the impact of these infections on intestinal structure and pathophysiology have yet been investigated. The key virulence factor identified to date for ETBF strains is a secreted heat-labile, ca. 20 kD metalloprotease toxin (B. fragilis toxin or BFT). Purified BFT and/or infection with ETBF stimulate secretion, rounding of the intestinal epithelial cells with disruption of cell-to-cell contacts and inflammation in both the small bowel and colon of animals. Similar observations have been accrued when intestinal epithelial cell models are treated with BFT in vitro. In these in vitro models, our data show reduced intestinal epithelial cell monolayer resistance, chloride secretion, inhibition of Na+ absorption, and secretion of the pro-inflammatory chemokine, interleukin-8. All of these data are consistent with the hypothesis that ETBF and BFT are causative agents of diarrheal disease. To begin to fill in the gaps in our understanding of ETBF disease, the Specific Aims of this proposal are: 1) to study in-depth the epidemiology of ETBF infections; and 2) to investigate the pathogenesis of ETBF infections with a particular focus on their impact on intestinal structure and function. ETBF will be identified in the stools of children and adults admitted to the diarrhea hospital of the International Centre of Diarrheal Disease Research in Bangladesh where ETBF infection has previously been shown to be significantly associated with diarrheal disease. Clinical data, acute and convalescent serum samples, stool studies to evaluate for evidence of inflammatory mediators and colon biopsies will be obtained and correlated to define the epidemiology and pathophysiology of the infection. We hypothesize that ETBF is an under-recognized intestinal pathogen accounting for a portion of previously undiagnosed inflammatory intestinal infections in both children and adults.