Candida Determinants of GI Tract Colonization

PROJECT SUMMARY Candida species are the primary cause of systemic fungal infections in nosocomial environments. Several of these species are common components of the human intestinal microbiota where they have been increasingly linked with mucosal disorders such as inflammatory bowel disease (IBD). Candida cells in the gut are also a critical reservoir for systemic infections as they can translocate out of this niche and disseminate throughout the body, particularly in immunocompromised individuals. There is therefore a pressing need to understand how Candida colonizes the GI tract and to define how changes to the commensal environment impact colonization behavior and the immune response. This project addresses the attributes of Candida cells that enables them to colonize the mammalian gastrointestinal (GI) tract. Despite the importance of Candida to both gut mucosal and systemic disease, a substantial knowledge gap exists in defining the molecular mechanisms that support colonization of the GI tract. In the case of Candida albicans (Ca), the most prevalent cause of fungal systemic disease, previous studies have indicated that yeast cells are optimal for gut colonization, whereas cells in the hyphal (filamentous) state are detrimental to commensalism but critical for systemic virulence. These studies are based on antibiotic- supplemented hosts, however, and our pilot experiments reveal the hyphal state plays an essential role in colonization of hosts that harbor an antibiotic-naïve microbiome. Furthermore, we demonstrate that candidalysin, a toxin secreted by hyphal Ca cells, is critical for colonization of the GI tract when bacteria are present, indicating that this factor supports competition with the bacterial microbiota. To build on these observations, we will examine how Candida morphology and co-regulated genes enable host colonization, while focusing on both Ca and the related species Candida parapsilosis (Cp). The Aims of this Project are (1) To define the effects of Candida morphology on fungal metabolism and intestinal fitness, (2) To determine the role of candidalysin in intestinal colonization, and (3) To use quantitative trait loci (QTL) mapping to identify traits impacting Candida commensalism. We emphasize that these experiments will use a wide variety of murine GI models that harbor either native bacterial populations or engineered microbial populations to determine how interkingdom interactions influence fungal gut commensalism. Together, these experiments will build on exciting preliminary experiments that overturn the prevailing paradigm that yeast-locked Candida cells are optimal for colonization, and that the hyphal-specific toxin candidalysin is a key gut colonization factor in addition to an established virulence factor. Given the importance of gut colonization to fungal-host interactions and systemic disease, these experiments will provide critical new insights into understanding how Candida species operate as human pathobionts.