Escherichia coli Fimbriae, Bacterial Persistence and Host Response Induction in the Human Urinary Tract

Abstract: Urinary tract infections (UTI) are among the most common bacterial infections in humans. Symptomatic UTIs may be acute, recurrent or chronic but the most frequent form of UTI is asymptomatic bacteruria (ABU). In ABU, the mucosa remains inert, despite the presence of large bacterial numbers in urine. The difference in disease severity reflects the virulence of the infecting strain and the propensity of the host to respond to infection. It is essential to understand the molecular basis of disease diversity and the molecular interactions between bacteria and host that determine asymptomatic carriage and the transition to disease. This thesis concerns the initial interactions between bacteria with the mucosal surfaces in the human urinary tract, and the bacterial factors involved in the breach of mucosal inertia. Specifically, the contribution of P and type 1 fimbriae to bacterial establishment and host response induction are investigated. The human bacteriuria model was used, since ABU protects against infections with more virulent strains. To study the role of adherence in UTI an Escherichia coli ABU strain, which does not express adherence factors, was transformed with DNA sequences encoding P or type 1 fimbriae and used for deliberate inoculation of patients with a history of recurrent UTI. P fimbriae were shown to provide a colonization advantage during the first days of bacterial establishment, as compared to the ABU strain lacking P fimbriae. In addition, P fimbriated E. coli were shown to trigger the innate mucosal responses, with increases in urine IL-6 and IL-8 concentrations, and recruitment of neutrophils. This effect was adhesion dependent, as shown by inoculations with a P fimbriated mutant lacking the PapG, adhesin. The P fimbriated bacteria adhered to uroepithelial cells in vivo, but adherence was not observed with the papG deletion mutant. After similar inoculations, type 1 fimbriae were not found to help the establishment of bacteriuria or the mucosal host response in the human urinary tract. This is surprising as type 1 fimbriae have been identified as important virulence factors in animal models of UTI. The results show that P fimbriae serve as independent virulence factors when expressed by an ABU strain, by promoting the establishment of bacteriuria and the innate host response, which is the cause of symptoms and tissue damage. P fimbriae thus fulfil the molecular Koch postulates as independent virulence factors in the human urinary tract. Type 1 fimbriae, in contrast, did not act as virulence factors in this model, and thus appear to serve a different function in man.