The importance of Escherichia coli fimbriae in urinary tract infection

University dissertation from Stockholm : Karolinska Institutet, Microbiology and Tumor Biology Center (MTC)

Abstract: Urinary tract infection (UTI) is a major bacterial infectious disease among women. Uropathogenic Escherichia coli is the most dominant causative agent. Clinical observations indicate that repeated cystitis induces a protective immune response and secretory IgA has been suggested as one of the candidates involved in the defence mechanisms against bladder infections. The aims of the present study were to study the importance of E. coli fimbriae in the pathogenesis of urinary tract infections and especially the role of the P-fimbria PapG class II tip adhesin in the adherence of E. coli to cultured human urogenital cells, the importance and protective effect of the PapG class II adhesin in establishing acute cystitis in an experimental model, and antibody response following experimental bladder infections. In addition we studied the induction of protective immunity via immunization with a fragment of the Type 1-fimbria adhesive FimC/H protein. We have demonstrated P-fimbriated specific adhesion in vitro to cultured human urogenital cells in both light microscopy and flow cytometry analyses. The PapG class II positive DS17 and JR1 adhered avidly, while the two mutants lacking PapG class II did not. We were able to inhibit adhesion with a soluble digalactoside-containing receptor analogue, indicating the specificity of the PapG-mediated adhesion. In an experimental cystitis model in primates, both the PapG class II positive E. coli strain DS17 and its two PapG class II negative mutants were able to induce bladder infections. DS17, but not the two mutants, gave rise to protection against subsequent bladder inoculation with both DS17 and the nonadhesive mutants. The acquired protection was correlated to a local production of secretory IgA in urine. In addition, a rise in IgA and IgG was observed in serum. Since the P-fimbriae are expressed in less then 50% of E. coli isolates causing cystitis, but the Type 1- fimbriae in a vast majority of these strains, we immunized monkeys with a FimH/C fragment derived from the Type 1-fimbria components. Three of the four immunized monkeys were protected against bladder infection when challenged with the Type 1-fimbriated strain NUM. One monkey developed a partial infection. None of four control monkeys were protected when challenged (one partial infection). The protection was correlated to levels of IgG against FimH in serum as well as in vaginal secretions. Furthermore, antibodies in serum and urine were able to inhibit adhesion of the strain NUM to cultured bladder cells. Our conclusions are that E. coli's virulence factors P- and Type 1-fimbriae are important in the pathogenesis of urinary tract infection. The PapG class II tip adhesin of P-fimbriated E. coli mediates specific adhesion to urogenital cells. A bladder infection with a PapG class II positive E. coli strain induces protection against subsequent challenge with homologous strain, while PapG class II negative mutants do not. The protective immune response following experimental bladder infections with a PapG class II positive strain correlates to levels of secretory IgA in urine. Immunization with a fragment of the FimC/H protein derived from E. coli Type 1-fimbriae mediates protection against cystitis caused by E. coli in a primate model Our results contribute to the understanding of the pathogenesis of lower urinary tract infections, and their induction of an immune response. This knowledge should be useful in future vaccine strategies.

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