Catheter-associated urinary tract infection (CAUTI) is the most common hospital-acquired infection worldwide, with an annual cost of approximately $451 million in the United States and an additional $2,900 per CAUTI- related bacteremia. Up to 86% of CAUTIs are polymicrobial, and CAUTI-related bacteremia is also often polymicrobial and carries a high mortality rate. Despite these clinical findings, experimental investigations have focused on single bacterial species in isolation. There is a fundamental gap in understanding of the influence of polymicrobial colonization on transition from asymptomatic bacteriuria to symptomatic CAUTI and the underlying mechanisms of progression from bladder and kidney colonization to bacteremia. Addressing these gaps in knowledge will be critical for developing new therapeutics and intervention strategies to reduce the incidence of CAUTI and enhance quality of life for catheterized individuals. The objective of this career development plan is to complement the candidate's background in bacterial polymicrobial interactions with training in experimental models of CAUTI, innate immunity, histopathology, clinical CAUTI research methods, and next generation sequencing techniques to establish an independent, translational research program investigating the pathogenesis of polymicrobial CAUTI. The central hypothesis of this proposal, guided by substantial preliminary data, is that polymicrobial colonization increases the incidence of bacteremia due to host cell damage from a potent innate immune response and synergistic production of virulence factors. This hypothesis will be tested through three specific aims that include utilizing a coinfection model developed by the candidate to 1) quantify bladder and kidney damage and identify host factors that contribute to cell damage and progression to bacteremia during coinfection, 2) identify bacterial virulence factors that contribute to bladder and kidney damage and progression to bacteremia during coinfection, and 3) analyze urine cultures and patient-level data from catheterized individuals to determine the influence of polymicrobial colonization on development of CAUTI and adverse outcomes such as bacteremia. An innovative, comprehensive model of polymicrobial infection will be developed through integration of experimental bacterial pathogenesis studies, innate immunity, histopathology, bioinformatics, clinical data, and patient samples. This research is significant because it will assess the influence of polymicrobial colonization on development of adverse and costly CAUTI complications, identify the most problematic bacterial species that correlate with adverse outcomes, and identify host and bacterial targets for therapeutic intervention. The knowledge gained will inform development of intervention strategies to reduce colonization by the most problematic bacterial species and to reduce the inappropriate prescription of antibiotics for asymptomatic bacteriuria. The distinguished mentoring team assembled by the candidate combined with the environment at the University of Michigan will provide exceptional training and support for the proposed study and the candidate's transition to independence.
Investigation of the pathogenesis of polymicrobial catheter-associated urinary tract infection (CAUTI) in catheterized nursing home residents and in an experimental mouse model is expected to identify potential targets for therapeutic intervention while also increasing understanding of the influence of polymicrobial colonization on progression of infection and CAUTI-related complications, such as the development of bacteremia. Thus, the proposed research is relevant to NIH's mission to enhance health, lengthen life, and reduce illness by contributing to improved understanding, prevention, and treatment of CAUTI, the most common hospital-acquired infection, and CAUTI-related bacteremia.
