Urinary tract infections (UTIs) are a significant health problem in the United States infecting 20% of the female population. The gram-negative bacteria E. coli causes the majority of UTIs and mouse models of UTIs have been established using clinical isolates of uropathogenic E. Coli (UPEC). One question that needs to be addressed in the pathogenesis of UTIs is how does the host recognize the UPEC and initiate an inflammatory response. The protein Toll Like Receptor (TLR) 4 has been shown to mediate recognition of lippopolysaccharide (LPS), produced by Gram-negative bacteria, on macrophages and dendritic cells. While the role of TLR4 on bone marrow derived cells in the immune system has been extensively studied, TLR4 function on epithelial cells has not been addressed. In fact, it is the epithelial cell that first encounters bacteria in UTIs. C3H/HeJ mice have a mutation in the TLR4 gene that renders the molecule unable to signal in response to LPS. Wild type C3H/HeN mice express functional TLR4 and produce a robust inflammatory response to UPEC. C3H/HeJ mice do not initiate this inflammatory response. Utilizing a reciprocal bone marrow reconstitution approach, the relative roles of TLR4 expression on the bone marrow derived cells and stromal/epithelial cells will be investigated. ? ?
