Pathogen of Enterotoxigenic Bacteriodes Fragilis Infect

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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.