The catheterized bladder environment promotes Efg1- and Als1-dependent Candida albicans infection

Abstract

Catheter-associated urinary tract infections (CAUTIs) are a serious public health problem and account for approximately 40% of hospital-acquired infections worldwide. Candida spp are a major causative agent of CAUTI (17.8%) – specifically Candida albicans – that has steadily increased to become the second most common CAUTI uropathogen 1 . Yet, there is poor understanding of the molecular details of how C. albicans attaches, grows in the bladder, forms biofilms, survives, and persists during CAUTI 2 . Understanding of the mechanisms that contribute to CAUTI and invasive fungal infection will give insights into the development of more effective therapies, which are needed due to the spread of antifungal resistance and complex management of CAUTI in patients that require a urinary catheter 3 . Here, we characterize the ability of five Candida albicans clinical and laboratory strains to colonize the urinary catheter, grow and form biofilm in urine, and their ability to cause CAUTIs using our mouse model. Analysis of C. albicans strains revealed that growth in urine promotes morphological transition from yeast to hyphae, which is important for invasive infection. Additionally, we found that biofilm formation was dependent on the presence of fibrinogen, a protein released on the bladder to promote bladder healing 4,5 . Furthermore, deletion of hyphae regulatory genes resulted in defective bladder and catheter colonization and abolished dissemination. These results indicate that novel antifungal therapies preventing the morphological transition of C. albicans from yeast to hyphae have considerable promise for the treatment of fungal CAUTIs.

Development and applications of a CRISPR activation system for facile genetic overexpression in Candida albicans

“…The C. albicans strains were incubated for 48h in human urine supplemented with bovine serum albumin (BSA) in fibrinogen-coated 96-well plates. Fibrinogen has been shown to be a critical protein for pathogen binding in CAUTIs, by providing a scaffold for biofilm formation and a nutritional source for pathogens (Flores-Mireles et al 2016;La Bella et al 2021;Andersen et al 2022). The ALS1 CRISPRa overexpression strain showed significantly greater biofilm formation compared to the corresponding wild-type strain (P < 0.0001; FIGURE 4c).…”