Friday, December 1, 2023
12/1/2023
Abstract Candida auris is an emerging fungal pathogen responsible for invasive, often multidrug-resistant infections and outbreaks worldwide. Unlike for many other fungal pathogens, C. auris infection is primarily nosocomial, driven by the propensity of C. auris to robustly colonize medical devices, implants, and abiotic surfaces that are proximal to patient quarters. C. auris can survive on abiotic surfaces for weeks, and many strains are resistant to commonly used antifungals and disinfectants, hindering decontamination efforts. The importance of this colonization to C. auris disease spread is demonstrated by intervention case studies associating reduction of infection incidence with removal of colonized fomites. C. auris can also form biofilms on surfaces, likely contributing to its resistance to decontamination. On a molecular scale, these processes require the initial first step of individual fungal cells physically attaching to a surface. While the regulation of attachment has been explored to a limited extent in related fungal species, no mechanistic studies have investigated the molecular machinery governing initial attachment in C. auris. Furthermore, while C. auris encodes genes homologous to characterized Candida albicans ALS and IFF/HYR family adhesins, proteins which have been implicated in attachment in other fungal species, our findings indicate none of these genes substantially contributes to attachment to abiotic surfaces in C. auris. Instead, we have identified B9J08_001458, a novel class of adhesin specifically encoded by C. auris with no characterized homologs. Deletion of B9J08_001458 substantially and significantly reduces C. auris adhesion. Furthermore, our preliminary findings suggest natural transcriptional variation of B9J08_001458 among C. auris isolates is linked to natural variation in adhesive potential. The goal of this proposal is to identify the functional and regulatory mechanisms of C. auris adhesion and explain the variability in adhesion in different C. auris clinical isolates. Our hypothesis is that C. auris regulates an adhesive cell surface profile primarily through expression of the putative novel adhesin B9J08_001458, and that transcriptional control of this adhesin explains adhesive variation amongst C. auris isolates. To address this hypothesis, we will leverage our global genetic and transcriptomic datasets to identify transcription factors targeting B9J08_001458. Our findings also suggest B9J08_001458 is regulated through the SWI/SNF chromatin remodeling complex; we will characterize this layer of transcriptional regulation by comparing chromatin states between wild type cells and mutants deficient in SWI/SNF function. We will then investigate the impact of genetic variants driving differential expression of B9J08_001458 amongst diverse C. auris isolates using genome wide association studies. The findings of this proposal will provide a scientific foundation for the rational development of decontamination and infection control protocols against C. auris, potentially mitigating the disease burden of this fungus.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
