Abstract Candida auris is an emerging fungal pathogen causing invasive infections worldwide with a high mortality rate. Unlike other fungal pathogens, it is frequently hospital-acquired and easily transmit within healthcare facilities, making it a critical and urgent public health concern. A unique virulence trait of C. auris is its ability to achieve extremely high levels of skin colonization, which not only serves as a source for nosocomial transmission but also as a risk factor for the development of subsequent life-threatening bloodstream infections. In the model fungal pathogen Candida albicans, tissue adhesion and invasion are mediated by cell surface- exposed proteins known as adhesins, which include the agglutinin-like sequence (ALS) protein family and hyphal-regulated cell wall (Hyr/Iff) protein family. C. auris encodes genes homologous to characterized C. albicans ALS and Hyr/Iff adhesin families. While the function and regulation of adhesins in tissue adhesion and invasion have been explored to a limited extent in C. albicans, no mechanistic studies have investigated the molecular machinery governing skin colonization in C. auris. C. auris clinical isolates identified so far are divided into five independent clades, with Clades I, III, and IV being pathogenic and associated with outbreaks of invasive infections. I, and others, have identified clade-specific abilities in colonizing skin by C. auris: Clade IV shows higher skin colonization compared to Clade I even though they encode the same set of adhesin genes. Therefore, I hypothesize that there is clade-specific genetic circuitry governing skin colonization in C. auris. To address this hypothesis, I will leverage the molecular genetic tools developed by our lab and my established in vitro keratinocyte and in vivo animal models to determine the genetic mechanisms underlying skin colonization in both Clade I and Clade IV. My preliminary data suggest that Clade I relies on specific adhesin genes to adhere to keratinocytes. I will examine their roles in skin colonization using the in vivo murine model. I also identified that Swi1, a component of the SWI/SNF chromatin remodeling complex, positively regulates the transcription of adhesin genes in Clade I. I will characterize this transcriptional regulation by comparing nucleosome occupancy at promoters of critical adhesin genes in both wild-type and SWI/SNF-deficient mutants, along with assessing SWI/SNF enrichment. To investigate mechanisms contributing to the increased skin colonization in Clade IV, I will first define the function of individual adhesins in keratinocyte adherence and in vivo skin colonization by generating targeted mutations of adhesins in this clade. I will then employ an unbiased forward genetics screen using high-throughput imaging-based analysis to identify additional genes required for skin colonization in Clade IV. This approach has led to the discovery of two factors that substantially contribute to keratinocyt...