Understanding the role of catheter-associated protein deposition in the development of CAUTI

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PROJECT SUMMARY: Modern healthcare has implemented medical devices to help and improve the life quality of people with chronic and lifestyle diseases. Paradoxically, although these devices are successful in achieving their purpose, they make the patient susceptible to infections. Urinary catheters are among the most widely used medical devices, and currently, catheter-associated urinary tract infections (CAUTI) are the most common healthcare-associated infection (HAI) worldwide, accounting for 40% of all HAIs. In addition, the treatment and control of CAUTI is becoming increasingly challenging due to the rise of antibiotic-resistant pathogens. Critically, CAUTIs are very different from uncomplicated urinary tract infections (UTIs), exhibiting unique clinical and pathological manifestations, as well as causative organisms. For example, in uncomplicated UTI, E. coli accounts for >95% of the causative agent, whereas in CAUTI, urinary catheterization allows pathogens such as Enterococcus spp., Staphylococcus aureus, Candida spp., Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumanii to colonize the bladder, something that otherwise would not occur. Given that the frequency of catheter usage is only expected to increase due to both an aging population and medical advances, it is imperative to understand the pathophysiology of CAUTI if we are to develop ways to treat and/or prevent it. Recent work has found that urinary catheterization elicits bladder inflammation and mechanically disrupts the host defenses, compromising the host for microbial colonization. Further findings in mice and humans have shown that fibrinogen (Fg) is released and accumulated in the bladder to heal the damaged tissue. Fg is also deposited on catheters, coating them and forming a platform for colonization by CAUTI-associated pathogens. It was found that Fg levels modulate outcome of the infection and, in the absence of Fg, E. faecalis is unable to stick to the catheter and colonize the bladder. On the other hand, high Fg levels enhance enterococcal bladder and catheter colonization. This suggests that protein deposition on urinary catheters is a key factor for microbial infection. This proposal tests the hypothesis that by controlling the amount of protein deposition on the surface using a novel liquid surface coating, we will be able to control the rate and extent of uropathogen biofilm formation, urinary tract colonization, and systemic dissemination, as well as the inflammation response. Through a combination of material modification, proteomics, histological, and immunological approaches with a mouse model of CAUTI, we will: 1) develop liquid-infused catheters that control protein deposition; 2) assess their contribution in reducing protein deposition and biofilm formation in vitro; and 3) characterize in vivo how protein deposition modulation affects biofilm formation, the outcome of infection, and inflammation. Understanding the role of protein deposition in promoting pathogen-material-host interactions will provide new perspective in the establishment and progression of CAUTI, generating key insights into the development of alternative treatments that do not contribute to microbial resistance.