Delineating host response to central venous catheter associated Candida albicans biofilm infections, and development of novel therapeutics to combat drug resistant biofilms

Abstract Candida albicans causes half of all invasive fungal infections in humans. It adheres to indwelling medical devices and develops into drug resistant multilayered community of cells called biofilms, which serve as a reservoir of continuing infections. While host response to mucosal and disseminated candidiasis is well studied, little is known on the immune response to C. albicans biofilms on catheters. We hypothesize that discovering virulence factors of biofilm cells, and delineation of the host immune response to the biofilm, can inform therapeutic strategies aimed at attenuation of biofilm-associated disseminated candidiasis in the host. For this we will use a rat central venous catheter model of biofilm infection. To understand the biofilm environment of catheter- infected cardiovascular tissue, we will utilize a new technology called Visium 10X Spatial Genomics, that provides a spatial “atlas” of all genes (host and pathogen) expressed during an active infection that can be visualized and analyzed simultaneously, without compromising tissue architecture. Following this, role of certain genes and proteins will be validated in in vitro, and ex vivo assays using endothelial cell lines, by immunohistochemistry, and evaluated in vivo for their role in biofilm clearance. Furthermore, we will assess the efficacy of two repurposed FDA-approved small molecules (that have previously demonstrated activity in mucosal models), for their promise as anti-biofilm drugs. Indeed, biomarkers of host response identified from aim 1 will be measured post drug treatment, to correlate eradication of infection with the host response. Overall, our studies will unearth the host response to central venous catheter associated biofilms, and investigate the potency of two promising compounds in eradicating biofilms.