| The epithelial cells lining mucosal surfaces are frequently the first host cell type to come into contact with potential bacterial pathogens. In addition to serving as a barrier to pathogen entry, epithelial cells can also produce cytokines, chemokines, and antimicrobial peptides following interactions with bacteria. However, the means by which epithelial cells recognize bacterial pathogens are not well characterized. To better understand the contribution of epithelial activation to innate host defenses we utilized the urinary tract infection experimental system. Urinary tract infections (UTIs) are one of the most common mucosal infections in the United States. The majority of UTIs are caused by Escherichia coli. In order to cause disease in the urinary tract uropathogenic E. coli (UPEC) must be able to bind to bladder epithelial cells, an event dependent on type 1 pili. Type 1 pili are surface adhesive organelles expressed by almost all strains of UPEC, which mediate both attachment to and invasion of bladder epithelial cells. E. coli expressing type 1 pili elicit significantly more epithelial cytokine production than do nonpiliated isogenic strains. We have defined a novel mechanism in which the activation of bladder epithelial cells by LPS is enhanced by type 1 pilus-mediated bacterial invasion. Moreover, we have demonstrated that the recognition of E. coli by bladder epithelial cells is mediated by toll-like receptors (TLRs) and CD 14. Consistent with this, mice deficient in the LPS receptor, TLR4, are unable to efficiently clear bacteria from the bladder following infection with UPEC. However, since these mice are globally deficient in TLR4 we performed bone marrow transplants between TLR4 wildtype and TLR4 mutant mouse strains to separate the function of epithelial/stromal cells from hematopoietic cells, such as macrophages and neutrophils, with respect to their contribution to innate host defenses in the bladder. The results demonstrated that TLR4 is required in both the epithelial/stromal and hematopoietic compartments to effectively clear bacteria during an acute UTI. Despite the formidable array of innate defenses in the bladder UPEC is able to persist in an intracellular environment within the bladder epithelium for up to 3 months after the acute infection. During this time, these persistent bacteria can re-establish an acute infection, which may relate to the clinically relevant issue of recurrent UTIs. Together these investigations have dramatically improved our understanding of UTI pathogenesis and may facilitate the development of new approaches to the therapy of this very common infectious disease. |
