Catheter-associated urinary tract infections (CAUTIs) are one of the most common nosocomial infections and if untreated can lead to serious complications including bacteremia and death. Enterococcus faecalis is a leading causative agent of CAUTI and its ability to adhere and persist within the host along with its multiple antibiotic resistances makes it difficult to prevent and treat. Furthermore, E. faecalis can form biofilm and grow despite a robust inflammatory response during CAUTI. The molecular details of how E. faecalis adheres, grows in the bladder, forms biofilm and the importance of biofilm in persistence in CAUTI are not well understood. This project will use a recently optimized model of E. faecalis CAUTI to understand how interactions between the E. faecalis Epb pilus and fibrinogen contribute to disease. Important questions to be addressed include a molecular analysis of how the EbpA subunit of the pilus binds to fibrinogen and the importance of this interaction to CAUTI. Mutants defective for biofilm formation in vitro are fully capable of forming biofilm in murine CAUTI, suggesting that standard biofilm models do not reproduce relevant in vivo conditions. This project will evaluate a new model of fibrinogen-supplemented urine biofilms to determine if genes required for biofilm in this model are also required for biofilm in murine CAUTI and will test the importance of biofilm in causing disease. Finally, we have data to suggest that an EbpA subunit-based vaccine protects against murine CAUTI and that immunized animals generate antibody that blocks EbpA-fibrinogen binding. The project will test the protective efficacy of various EbpA sub-domain and peptide vaccines in comparison to formulations that use other pilus sub- units. Combined with passive transfers of sera from immunized animals and characterization of antibody responses, it will be possible to specifically test whether the mechanism of protection depends on blocking EbpA-fibrinogen binding. The data generated by this project will provide significant new insights into the pathogenesis of CAUTI with direct application to the development of new modalities of therapy. .
Up to 30% of short-term and up to 100% of long-term patients with urinary tract catheters will develop a catheter-associated urinary tract infection (CAUTI). One of the most common types of bacteria causing CAUTI is Enterococcus faecalis, which is difficult to treat because of its resistance to multiple antibiotics. This project will use a novel mouse model of CAUTI to determine how E. faecalis uses hair-like appendages known as pili to attach to catheters and how it grows on the catheter and on bladder tissue and how vaccines that incorporate pilus proteins provide protective immunity. This information can be used to develop new therapeutic agents to prevent CAUTI.
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|Flores-Mireles, Ana L; Walker, Jennifer N; Caparon, Michael et al. (2015) Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol 13:269-84|
|Flores-Mireles, Ana L; Pinkner, Jerome S; Caparon, Michael G et al. (2014) EbpA vaccine antibodies block binding of Enterococcus faecalis to fibrinogen to prevent catheter-associated bladder infection in mice. Sci Transl Med 6:254ra127|