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

Abstract

Graphical Abstract Highlights d Candida albicans colonizes the gastrointestinal tract as a mixture of yeast and hyphae d A C. albicans hyphal gene network that promotes virulence inhibits commensal fitness d Commensal fitness is inversely related to expression of hypha-specific virulence effectors d Hosts may tolerate yeasts while restricting pathogenic hyphae in the gut In Brief C. albicans is a fungal commensalpathogen 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. SUMMARYCandida 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.Carlisle, P.L., and Kadosh, D. (2013). A genome-wide transcriptional analysis of morphology determination in Candida albicans. Mol. Biol. Cell 24, 246-260.

Setting Up Home: Fungal Rules of Commensalism in the Mammalian Gut

“…The finding by Witchley et al (2019) that major hyphal transcriptional activators limit the commensal fitness of C. albicans is mirrored by the results of Tso et al (2018). In that study, the authors employed an experimental evolution approach, under which C. albicans was inoculated in the gut of antibiotic-exposed mice or infant mice, which are permissive for C. albicans longterm colonization, and serially passaged via weekly fecal transplantation.…”

“…Candida albicans is a commensal fungus of the human gut, but also causes life-threatening systemic infections. Recent studies published in Cell Host & Microbe (Witchley et al, 2019) and Science (Tso et al, 2018) provide insights into the determinants of C. albicans commensal fitness within the mammalian gut.…”

“…While the contribution of yeast-to-hypha transition in pathogenicity is well recognized, less is known about the fungal factors that modulate commensal fitness within the mammalian gut. In this regard, an elegant study by Witchley et al (2019) in this issue provides the foundation for a deeper understanding of the molecular determinants of C. albicans' commensalism. The authors show that major transcriptional activators of the yeast-to-hypha transition inhibit commensal fitness.…”

“…A first insight provided by Witchley et al (2019) is via the adaptation of a fluorescence in situ hybridization (FISH)based approach to accurately visualize C. albicans morphologies within the fungal-colonized mouse gut. This approach revealed hyphal formation throughout the gut, with greater abundance of hyphae over yeast cells in distal intestinal regions that are enriched for known hypha-inducing signals such as hypercarbia, hypoxia, and N-acetyl glucosamine (Noble et al, 2017).…”

“…To understand the genetic basis of the adaptation, the authors sequenced 28 different adapted C. albicans strains, evolved from the same ancestral strain, and discovered loss-of-function mutations in the major activators of hyphal formation Flo8, Efg1, and Rob1. Efg1 and Rob1 were also identified as fitness mediators by Witchley et al (2019). Flo8, the most frequently affected locus among all strains (22/28) in the study by Tso et al (2018), was not evaluated by Witchley et al (2019) as the flo8 mutant strain was not included in their library.…”