Understanding the Effects of the Inflammatory Response During Catheter-Associated Urinary Tract Infections: Roles of Fibrin(ogen) and Interleukin-6 in Promoting Infections and Targeted Anti-Inflammatory Therapeutics to Mitigate Infections

In the Flores-Mireles Lab, we focus on understanding catheter-associated urinary tract infections (CAUTI). Specifically, how the host response during varying infections from multiple pathogens in mono- and polymicrobial infections. Unfortunately, many CAUTI pathogens are resistant to antimicrobials and antibiotics only drive resistance even further. The fact that diverse pathogens can cause CAUTIs is alarming. CAUTIs present different pathophysiologies from uncomplicated urinary tract infections (uUTIs), where one pathogen causes the vast majority of the infections. The first chapter focuses on comparing and contrasAng the eAology and pathophysiologies of uUTI and CAUTI . Our work has tirelessly investigated how catheter-induced bladder inflammation promotes recruitment of fibrinogen (Fg) into the bladder, which is critical for CAUTI establishment. In chapter 2, I provide insight on the outcomes fibrin(ogen) has in vivo and provide evidence that being able to clear soluble fibrinogen (soluble Fg) and its polymerized form (fibrin; Fn) is crucial for being able to clear infections and protect hosts from bloodstream infections, which CAUTIs often lead to. Additionally, by beginning to dissect the inflammatory response of the bladder during catheterization and infections, I was able to target one specific marker (interleukin-6; IL-6), understand how IL-6 can both promote and inhibit, identify a feedback loop IL-6 is complexed in with Fg, and how IL-6 pro-inflammatory roles lead to more severe infections. Additionally, by targeting IL-6’s pro-inflammatory role through either Sgp or Dex, which represent two known drugs available to patients, were we able to repurpose therapeutics and mitigate CAUTIs as an antibiotic-sparring treatment. This led to the development of a novel catheter that ultimately inhibits both aspects of this dissertation, inflammation and Fg presence in the catheterized bladder. These findings not only improved our understanding of the CAUTI field, but also the IL-6 field, and provide key information to improve or start the progress of antibiotic-sparring therapies to improve patient outcomes.