New insights into Escherichia coli pathogenicity: novel targets for antivirulence and immunomodulation approaches against urinary tract infections – UTI-TOUL

Urinary Tract Infections (UTIs) are among the most common infections worldwide, affecting one in two women. Symptomatic UTIs may be acute or recurrent, but Asymptomatic BacterUria (ABU) often also occur. Uropathogenic Escherichia coli (UPEC) are the bacteria responsible for 50–90% of all UTIs. Introduction of UPEC into the mammalian urinary tract evokes a well-described inflammatory response. Interestingly, a strong relationship exists between inflammation and iron homeostasis. Iron is particularly deficient in the urine; and for successful intracellular survival in bladder epithelial cells, UPEC must obtain iron from the host cell. We hypothesize that a subversion of host inflammation, innate immunity and iron homeostasis by UPEC takes place during UTI development. Increasing literature indicates that bacterial metabolites may have important consequences on host epithelial cell physiology. For instance, siderophores, high-affinity iron-chelating compounds secreted by bacteria, play a critical role in UTI; but we and others have shown that UPEC and ABU produce a rich and diverse repertoire of secondary metabolites with potent biological function, such as the genotoxin colibactin. We hypothesize that the quantitative and qualitative differences in the production of secondary metabolites between UPEC and ABU strains could have consequences on the severity of the UTI. These specific metabolites may “remodel” the innate and adaptive immune response in the urinary tract together with inflammation and host iron homeostasis that could play a key role in determining susceptibility to UTI. Our project is aiming at elucidating the role of secondary metabolites produced by UPEC and ABU (siderophores, genotoxin colibactin, other metabolites synthesized via these biosynthetic synthesis pathways…) in the physiopathology of UTI, with a specific focus on host immune response and iron metabolism. Using mouse models of acute and chronic UTI, we will provide novel insights into UPEC virulence, and will decipher the impact of host iron metabolism and inflammation in the disease severity and progression. Furthermore, to reinforce the impact of virulence factors and inflammation modulation in UPEC pathogenicity, novel iron homeostasis inhibitors and immunomodulation drugs will be tested as potential novel therapies to treat UTI. Firstly, we expect to identify potential novel targets for further alternative strategies to treat UPEC-induced UTI, to develop innovative solutions to fight the disease, and to mitigate the problem of the emergence of pathogenic microorganisms multi-resistant to antibiotics. Secondly, we expect to demonstrate the proof of concept of new drugs efficacy by modulating immune response and iron homeostasis. This project brings together 3 partners with complementary expertise in microbiology (Partner1), in the regulation of iron metabolism (Partner3) and in drug development in infection disease (Partner2). The association of Partner2, VibioSphen, a biotechnology company developing innovating solutions to tackle infectious diseases and preclinical infectious models, reinforces this partnership and offers the greatest opportunity to achieve the above-mentioned objectives.