Role of TLR4 in Escherichia coli urinary tract infection

Sammanfattning: In this thesis we have used P fimbriated E. coli as a model to investigate the mechanisms of bacterial recognition and cell activation by the urinary tract (UT) epithelium. We show that Toll like receptor 4 (TLR4) is crucial for the recognition and host response to P fimbriated E. coli. This response was independent of LPS and did not require CD14. TLR4 was abundant on epithelial cells throughout the human urinary tract, while CD14 was absent from this compartment, as shown by immunohistochemistry on mucosal biopsies. In vitro infection of the biopsies with uropathogenic E. coli triggered a cytokine response. This response was absent when using avirulent control strains, showing that the human urinary tract epithelium is able to discriminate non-virulent strains from pathogens. We propose a mechanism for the discrete recognition of P fimbriated E. coli in which the glycosphingolipid (GSL) receptors for P fimbriae are needed in addition to TLR4, for cell activation. P fimbrial binding to GSLs induces ceramide release from the membrane. This activates TLR4, suggesting that ceramide might act as a signaling intermediate between the GSLs and TLR4. The TLR4 dependent intracellular signaling pathway in response to P fimbriated E. coli was shown to require the adaptors TRIF/TRAM but not MyD88/TIRAP. The results show an example of discrete recognition of pathogenic bacteria. They provide a mechanism for how epithelial cells can discriminate avirulent strains from pathogens and control the host response in relation to the type of infecting agent.