Understanding the molecular mechanisms regulating fungal colonization and disease in the mammalian intestinal niche

PROJECT SUMMARY The Fungal Colonization Resistance (FunCoRe) Program Project “Understanding the molecular mechanisms regulating fungal colonization and disease in the mammalian intestinal niche” focuses on developing an integrated and predictive model of the molecular, cellular, and metabolic determinants of Candida gastrointestinal (GI) colonization and its relationship to life-threatening invasive candidiasis. FunCoRE consists of 3 projects and 3 cores and combines in-depth studies of hematopoietic cell transplant patients with defined Candida colonization phenotypes and curated clinical data with experiments in reductionist experimental models of Candida GI colonization. The patient cohort serves as a source for a large Candida strain collection and for fecal metabolite abundance measurements that are harnessed in projects and cores. Project 1 emphasizes the role of morphology, virulence factors, and strain-specific genomic features on C. albicans and C. parapsilosis GI colonization. Project 2 characterizes immune signaling pathways and cell types (Paneth cells, innate lymphoid cells) that mediate Candida colonization resistance. Project 3 focuses on the bacterial microbiota and their biosynthetic capabilities, with a focus on short- and medium-chain fatty acids, to determine direct and indirect mechanisms of colonization resistance. A Gnotobiotic Core enables deep mechanistic dissection of the contribution of individual molecular, cellular, immune pathways, and commensal bacteria to colonization phenotypes. A Mathematical Modeling Core ties all 3 projects together and will generate predictive models of Candida GI colonization that incorporate specific fungal attributes, the bacterial microbiota and metabolites, and host immune parameters. Modeling outputs will be iteratively tested and refined in collaboration with the experimental projects to explore the overall hypothesis that the synergy of experimental and modeling approaches will reveal fungal, immune-mediated, and metabolic determinants of Candida GI colonization and colonization resistance which can inform and be harnessed for therapeutic strategies to limit invasive candidiasis. Aim 1 will investigate the Candida functional capacities that promote GI colonization; Aim 2 will interrogate host cell networks and colonization-relevant metabolites at the host-Candida interface; Aim 3 will develop an integrative model of Candida colonization resistance that identifies ecologic, immune, and metabolic targets to restore and enhance Candida colonization resistance. Successful completion of these aims will be supported by a strong Administrative Core management plan to facilitate communication and collaboration between projects and cores. The breadth and complementarity of expertise, multidisciplinary approaches, track record of collaboration, and commitment to establish a mentored undergraduate internship program represent signature features of FunCoRe. Insights will inform benchtop-to-bed strategies to formulate novel interventions that can shape the fungal communities in the GI niche to prevent invasive candidiasis and improve patient outcomes.