Urinary tract infection : pathogenesis and complications

Abstract: Urinary tract infections (UTI) are one of the most common infections in women and children worldwide. If not diagnosed and treated appropriately, it may lead to severe illness and long-term complications. The economic impact caused by UTI on society is significant. In addition, bacterial resistance to common antibiotics is spreading at a high rate. Recent years, the understanding of the host-pathogen interaction and activation of the immune response in the urinary tract has increased considerably. However, there is still a lack of understanding how these basic molecular events can be translated into clinical practise. In this thesis, the complex interaction between the uropathogenic E. coli and the urinary bladder and the kidney epithelium is described in the context of novel findings about virulence factors, immune response and complications following UTI. In the first study, we investigated the chemokine profile in the kidneys of mice with pyelonephritis and the impact of IL-1β by using an IL-1β knockout mouse and renal cell lines. We could show a robust induction of IL-8/MIP-2 and of the chemokines MCP-1 and RANTES, not previously associated with bacterial infection. In the second study, we described a new set of molecules involved in UTI pathogenicity, the metalloproteinase MMP-9 and its natural inhibitor TIMP-1. They increased in experimental pyelonephritis in mice and were found to be expressed by immune cells and resident renal cells. In children with pyelonephritis, we could link TIMP-1 to an increased risk of renal scarring. In the third study, we investigated the virulence factor cytotoxic necrotizing factor (CNF1), commonly found in uropathogenic E. coli. Increased inflammatory reaction could be attributed to CNF1 in vitro; however, urine from patients with UTI caused by CNF1 positive or negative E. coli showed no difference in inflammatory response. Thus, the difference seen in vitro is probably of minor importance in vivo in comparison to other virulence factors of the uropathogenic E. coli. In the last paper, we demonstrated that women supplemented with vitamin D had a stronger response of the antimicrobial peptide cathelicidin when biopsies from the urinary bladder were infected ex vivo. We also showed that normal urinary bladder cells were able to activate 25 hydroxyvitamin D3 to its functional form 1,25 dihydroxyvitamin D3, indicating a role for locally produced vitamin D in the urinary bladder. In addition, bladder cells increased their cathelicidin stores after vitamin D treatment and exerted antibacterial properties against uropathogenic E. coli. In conclusion, this thesis presents new findings about host-microbe interaction in the urinary tract, the immune response and post-infectious complications of UTI. MMP-9, TIMP-1 and the chemokines IL-8/MIP-2, MCP-1 and RANTES were produced in the kidneys during pyelonephritis. IL-1β and TIMP-1 affected the severity of infection and renal scarring. The E. coli toxin CNF1 influenced the immune response only in vitro, but did not seem to influence inflammation in vivo. Finally, treatment with vitamin D increased the antibacterial properties of the uroepithelium by induction of the antimicrobial peptide cathelicidin.

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