Mechanism of dysbiosis caused by AE Pathogens

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 DESCRIPTION (provided by applicant): Attaching and effacing (AE) pathogens are an important cause of diarrheal disease in both high-income and low-income countries. AE pathogens use an outer membrane adhesin, termed intimin, to bind to a receptor protein, termed translocated intimin receptor (Tir), which the pathogen injects into epithelial cells using type III secretion system (T3SS). The resulting intimate attachment to epithelial cells provides AE pathogens access to a microenvironment that boosts their growth through unknown mechanisms. This results in changes in the composition of gut associated microbial communities that are characterized by a dominance of the AE pathogen. The question of which mechanisms are responsible for these changes in the microbiota composition represents a high-impact topic that will be addressed in this application. Our central hypothesis is that T3SS-mediated intimate attachment to host epithelial cells provides AE pathogens with access to oxygen for respiration, thus providing a substantial advantage over fermenting commensal bacterial and driving dysbiosis in the gut. We will test different aspects of our hypothesis by investigating the mechanism by which the C. rodentium T3SS promotes aerobic respiration (Aim 1) and determining the consequences of aerobic respiration during competition of C. rodentium with the gut microbiota (Aim 2). The proposed work is innovative because it is among the first to elucidate molecular mechanisms that control the balance between AE pathogens, the host and its microbiota. It is our expectation that successful completion of the proposed work will usher in a major conceptual advance by demonstrating that intimate attachment to epithelial cells confers a fitness advantage by providing AE pathogens with access to oxygen for growth.