Fungal regulatory systems directing mammalian host colonization

ABSTRACT The fungus Candida albicans is a ubiquitous member of the human gut microbiota, yet also causes mucosal disease and life-threatening disseminated infections. The research program that I describe here seeks to understand the links between the fungus' facet as intestinal commensal and its ability to proliferate in disparate organs. The program is built upon recent findings from my laboratory which ¾ through systematic genetic screens conducted in mouse models of gut colonization, oropharyngeal candidiasis and disseminated infections ¾ reveal that fungal genetic determinants of fitness in the gut also shape the interactions of the fungus with other tissues. The proposed study encompasses three specific directions: (i) elucidating the mechanisms of activation and inhibition of a regulator of fungal sphingolipids which is active in the gut and inside human neutrophils; (ii) defining the effector genes and extracellular cue(s) of a regulator that promotes binding to intestinal mucus; and (iii) identifying C. albicans gene products that enable the fungus to inhabit the intestinal mucus layer. The proposed research is expected to reveal basic principles underlying the interplay between mammalian host and the most prominent fungus residing in humans.