Induction of innate immune responses by Escherichia coli and purified lipopolysaccharide correlate with organ- and cell-specific expression of Toll-like receptors within the human urinary tract

Mucosal epithelial linings function as physical barriers against microbes. In addition, they participate in the first line of host defence by producti on of a variety of proinflammatory mediators when exposed to microbes and m icrobial agents. Here, we use a human urinary tract infection model to demo nstrate that organ- and cell-specific innate responses induced by lipopolys accharides (LPS) present on Gram-negative bacteria correlates with the expr ession of Toll-like receptor 4 (TLR4). The presence of TLR4 on human bladde r epithelial cells enables them to rapidly respond to bacterial infections in vitro and in vivo. In contrast, TLR4 is not expressed on human proximal tubule cells isolated from the renal cortex, which may explain the cortical localization of bacteria in pyelonephritis. TLR4-negative renal epithelial cells, A498, are non-responsive to purified LPS, however, they respond to viable bacteria via a mannose-sensitive attachment-mediated pathway. To ide ntify LPS components recognised by bladder epithelial cells, a bacterial li pid A mutant and LPS of different chemotypes were tested. Full interleukin 8 induction required hexa-acylated lipid A and was decreased by between 50% and 70% in the presence of O-antigen. Taken together, we propose that mult iple independent pathways, which are organ- and cell-specifically expressed , mediate bacterial recognition and determine the outcome of innate respons es to infection.