Escherichia coli P fimbriae utilize the Toll-like receptor 4 pathway for cell activation

Fimbriae mediate bacterial attachment to host cells and provide a mechanism for tissue attack. They activate a host response by delivery of microbial products such as lipopolysaccharide (LPS) or through direct fimbriae-depend ent signalling mechanisms. By coupling to glycosphingolipid (GSL) receptors , P fimbriae trigger cytokine responses in CD14 negative host cells. Here w e show that P fimbriae utilize the Toll-like receptor 4 (TLR4)-dependent pa thway to trigger mucosal inflammation. Escherichia coli strains expressing P fimbriae as their only virulence factor stimulated chemokine and neutroph il responses in the urinary tract of TLR4 proficient mice, but TLR4 defecti ve mice failed to respond to infection. Mucosal cells were CD14 negative bu t expressed several TLR species including TLR4, and TLR4 protein was detect ed. Infection with P fimbriated bacteria stimulated an increase in TLR4 mRN A levels. The activation signal did not involve the LPS-CD14 pathway and wa s independent of lipid A myristoylation, as shown by mutational inactivatio n of the msbB gene. Co-staining experiments revealed that TLR4 and the GSL receptors for P fimbriae co-localized in the cell membrane. The results dem onstrate that P fimbriae activate epithelial cells by means of a TLR4-depen dent signalling pathway, and suggest that GSL receptors for P fimbriae can recruit TLR4 as co-receptors.