Pathogen of Enterotoxigenic Bacteriodes Fragilis Infect

描述(申请人提供)：脆弱类杆菌是主要的 厌氧菌血症和腹内脓肿的原因。在过去15年中 多年来，越来越多的数据表明脆弱芽孢杆菌(称为 肠毒素脆弱杆菌或ETBF)在腹泻疾病中的致病作用 折磨着年幼的儿童和成年人。到目前为止，ETBF上可用的人类数据 感染仅限于评估流行病学相关性的研究。 出现腹泻和最近出现炎症性肠病的ETBF菌株 和血液感染。然而，与之相关的临床综合征(S) 肠道ETBF感染的定义不明确，这些感染的影响 对肠道结构和病理生理的影响尚未得到研究。钥匙 到目前为止，ETBF菌株的毒力因子是一种分泌的热不稳定因子， 约20kD的金属蛋白酶毒素(B.Fragilis毒素或BFT)。纯净的BFT和/或 感染ETBF刺激肠道上皮细胞分泌，变圆 细胞间接触中断和炎症的细胞 动物的小肠和结肠。类似的观察结果也出现在以下情况 体外培养肠上皮细胞模型，观察补肾活血方对其的影响。在这些In中 体外模型，我们的数据显示肠上皮细胞单层减少 抗性、氯离子分泌、抑制Na+吸收和分泌 促炎症的趋化因子，白介素8。所有这些数据都是一致的 假设ETBF和BFT是腹泻的病原体 疾病。为了开始填补我们对ETBF疾病的认识空白， 这项建议的具体目的是：1)深入研究流行性感冒的流行病学 ETBF感染；以及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 会在入院的儿童和成人的粪便中鉴定出来 年国际腹泻病研究中心腹泻医院 孟加拉国，此前ETBF感染已被证明是严重的 与腹泻病有关。临床资料、急性期和恢复期血清 样本，粪便研究，以评估炎性介质和 将获得结肠活组织检查并进行关联，以确定流行病学和 感染的病理生理学。我们假设ETBF是一个 之前认识不足的肠道病原体占了一部分 儿童和成人未确诊的炎症性肠道感染。

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.