Type 1 fimbriae deliver an LPS- and TLR4-dependent activation signal to CD14-negative cells

Fimbriae target bacteria to different mucosal surfaces and enhance the infl ammatory response at these sites. Inflammation may be triggered by the fimb riae themselves or by fimbriae-dependent delivery of other host activating molecules such as lipopolysaccharide (LPS). Although LPS activates systemic inflammation through the CD14 and Toll-like receptor 4 (TLRL4) pathways, m echanisms of epithelial cell activation by LPS are not well understood. The se cells lack CD14 receptors and are unresponsive to pure LPS, but fimbriat ed Escherichia coli overcome this refractoriness and trigger epithelial cyt okine responses. We now show that type 1 fimbriae can present an LPS- and T LR4-dependent signal to the CD14-negative epithelial cells. Human uroepithe lial cells were shown to express TLR4, and type 1 fimbriated E. coli strain s triggered an LPS-dependent response in those cells. A similar LPS- and fi mbriae-dependent response was observed in the urinary tract of TLR4-profici ent mice, hut not in TLR4- defective mice. The moderate inflammatory respon se in the TLR4-defective mice was fimbriae dependent but LPS independent. T he results demonstrate that type 1 fimbriae present LPS to CD14-negative ce lls and that the TLR4 genotype determines this response despite the absence of CD14 on the target cells. The results illustrate how the host 'sees' LP S and other microbial products not as purified molecules but as complexes, and that fimbriae determine the molecular context in which LPS is presented to host cells.