Alyssa Ann La Bella

Urinary catheterization, a frequent procedure in hospitals, nursing homes, and other healthcare facilities, is a primary driver of nosocomial infections. The most common of these are catheter-associated urinary tract infections (CAUTIs), which often progress to severe complication, sepsis, and ultimately death. The fungus Candida albicans is a primary causative agent of CAUTIs; yet, its tissue-specific pathogenesis remains poorly understood, which complicates development of efficient treatments. While Efg1 is a known virulence driver in CAUTI, its specific downstream targets within the unique bladder environment have not been defined. Here, we identify and validate the EFG1 regulon that is active during conditions that mimic the human catheterized bladder and, additionally, confirm the regulon by transcriptional profiling of catheters retrieved from patients with C. albicans infection. We found that this urine-specific signature is highly conserved in clinical samples, with Efg1-dependent genes being among the most robustly induced transcripts during active human infection. Furthermore, we characterized two of these key factors, ECE1 and EED1 , validating their roles in infection both in vitro in human urine and in vivo using a CAUTI mouse model. Elucidating this tissue-specific regulon offers a strategic roadmap for the development of targeted therapies to mitigate these ever-increasing life-threatening fungal infections.

Candidozyma auris is a high-priority, emerging fungal pathogen frequently isolated from urine in healthcare settings. These isolates are often associated with indwelling urinary catheters, a primary risk factor for catheter-associated urinary tract infections (CAUTIs). Despite its clinical prevalence, the mechanisms of C. auris colonization and pathogenesis within the bladder remain poorly understood. In this study, we screened C. auris isolates from diverse clades using an in vitro biofilm model and in vivo murine models of uncomplicated UTI and CAUTI. While in vitro biofilm formation varied among isolates, the presence of a catheter in vivo significantly enhanced fungal burden in the bladder. Notably, one strain (B11103) caused rapid systemic dissemination and mortality. To address this, we evaluated a liquid-infused silicone (LIS) catheter coating, which has previously shown efficacy against other uropathogens. The LIS coating significantly reduced C. auris attachment in vitro and, crucially, mitigated fungal burden on both the catheter and bladder tissue in vivo across all tested strains. For the hypervirulent B11103 strain, LIS catheters also significantly reduced dissemination to the kidneys and bloodstream. Furthermore, cytokine analysis revealed that C. auris CAUTI upregulates IL-6, CSF3, and CXCL1; importantly, this damaging inflammatory response was also dampened by the LIS catheter. These findings demonstrate that catheterization potentiates C. auris pathogenicity and identify LIS catheters as a promising, antimicrobial-sparing strategy to prevent colonization, systemic spread, and inflammation during C. auris CAUTI. IMPORTANCE: This research addresses the critical public health challenge posed by the emergence of Candidozyma auris, elucidating its pathogenesis in the urinary tract, the second-most common yet understudied reservoir. Here, we find that C. auris exhibits plasticity in its ability to form biofilms in urine and cause uncomplicated urinary tract infections (UTIs) and catheter-associated UTIs (CAUTIs). Importantly, we show that our liquid-infused silicone (LIS) catheters effectively disrupt this cycle by reducing fungal burden, preventing systemic spread, and dampening the damaging host inflammatory response. This work establishes the urinary tract as a critical niche for systemic entry and provides a validated strategy for infection prevention. Urinary catheters make C. auris dangerous, but this liquid-infused silicone coating is fighting back.

Catheter-associated urinary tract infections (CAUTIs) account for 40% of hospital-acquired infections (HAIs). As 20 to 50% of hospitalized patients receive catheters, CAUTIs are one of the most common HAIs, resulting in increased morbidity, mortality, and health care costs. Candida albicans is the second most common CAUTI uropathogen, yet relative to its bacterial counterparts, little is known about how fungal CAUTIs are established. Here, we show that the catheterized bladder environment induces Efg1- and fibrinogen (Fg)–dependent biofilm formation that results in CAUTI. In addition, we identify the adhesin Als1 as the critical fungal factor for C. albicans Fg-urine biofilm formation. Furthermore, we show that in the catheterized bladder, a dynamic and open system, both filamentation and attachment are required, but each by themselves are not sufficient for infection. Our study unveils the mechanisms required for fungal CAUTI establishment, which may aid in the development of future therapies to prevent these infections.

Catheter-associated urinary tract infections (CAUTIs) account for 40% of all hospital-acquired infections. Given that 20-50% of all hospitalized patients receive a catheter, CAUTIs are one of the most common hospital-acquired infections and a significant medical complication as they result in increased morbidity, mortality, and an estimated annual cost of $340-370 million. Candida spp . – specifically Candida albicans – are a major causative agent of CAUTIs (17.8%), making it the second most common CAUTI uropathogen. Despite this frequent occurrence, the cellular and molecular details of C. albicans infection in the CAUTI microenvironment are poorly understood. Here, we characterize fungal virulence mechanisms and fungal biofilm formation during CAUTI for the first time. We found that the catheterized bladder environment triggers Candida virulence programs and robust biofilm formation through Efg1-dependent hyphal morphogenesis and Als1, an Efg1-downstream effector. Additionally, we show that the adhesin Als1 is necessary for in vitro and in vivo C. albicans biofilm formation dependent on the presence of fibrinogen (Fg), a coagulation factor released in the bladder due to the mechanical damage caused by urinary catheterization. Furthermore, in the presence of Fg, overexpression of ALS1 in C. albicans led to enhanced colonization and dissemination, while deletion of ALS1 reduced both outcomes during CAUTIs. Our study ultimately unveils the mechanism that contributes to fungal CAUTI, which may provide more effective targets for future therapies to prevent these infections.