Candida albicans Morphogenesis Programs Control the Balance between Gut Commensalism and Invasive Infection

Candida albicans is a gut commensal and opportunistic pathogen. The transition between yeast and invasive hyphae is central to virulence but has unknown functions during commensal growth. In a mouse model of colonization, yeast and hyphae co-occur throughout the gastrointestinal tract. However, competitive infections of C. albicans homozygous gene disruption mutants revealed an unanticipated, inhibitory role for the yeast-to-hypha morphogenesis program on commensalism. We show that the transcription factor Ume6, a master regulator of filamentation, inhibits gut colonization, not by effects on cell shape, but by activating the expression of a hypha-specific pro-inflammatory secreted protease, Sap6, and a hyphal cell surface adhesin, Hyr1. Like a ume6 mutant, strains lacking SAP6 exhibit enhanced colonization fitness, whereas SAP6-overexpression strains are attenuated in the gut. These results reveal a tradeoff between fungal programs supporting commensalism and virulence in which selection against hypha-specific markers limits the disease-causing potential of this ubiquitous commensal-pathogen. [Display omitted] •Candida albicans colonizes the gastrointestinal tract as a mixture of yeast and hyphae•A C. albicans hyphal gene network that promotes virulence inhibits commensal fitness•Commensal fitness is inversely related to expression of hypha-specific virulence effectors•Hosts may tolerate yeasts while restricting pathogenic hyphae in the gut C. albicans is a fungal commensal-pathogen of mammals. Witchley, Penumetcha et al. show that a filamentation program that promotes fungal virulence inhibits commensal fitness in the gut. This effect is mediated not by cell morphology, but by expression of hypha-specific virulence factors that appear to trigger negative selection.