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.
