UCSF

Candida albicans is the most common cause of fungal disease in humans, however it more typically exists as a benign commensal among the mammalian gut, genitourinary tract, and skin microbiota. Notably, C. albicans exhibits an unusual degree of phenotypic plasticity, embodying eight distinct yeast morphotypes. However, it is not well understood if, where, how, or why phenotypic switching occurs in the host. In this dissertation we show that different C. albicans morphotypes are suited for distinct niches within the host and define some of the environmental cues and signaling pathways that regulate C.albicans phenotypic transitions. Within the GI tract, C. albicans undergoes a developmental transition from oval white cells to an elongated GUT cell type that is metabolically specialized for this niche. To test the hypothesis that different C. albicans cell types are optimized for growth in distinct host niches we performed a comprehensive study comparing all eight cell types in commensal and disease models of skin colonization, cellulitis, and oropharyngeal candidiasis. We found that white cell types have enhanced fitness in all three models, while GUT and grey cells are attenuated in these models. Opaque cells are attenuated in the skin models, but are potentially more virulent on the tongue. These data suggests that white cells are versatile and able to colonize and infect multiple host niches, while GUT cells are acutely specialized for growth in the GI tract. Potential roles for opaque and grey cell types remain to be elucidated. In order to determine the host signals and fungal signaling pathways that control the white-GUT switch and drive commensalism, we developed an in vitro system to induce switching behavior and screened a library of C. albicans signaling mutants. We identified three fungal signaling pathways (Hog1, Rim101, and PKA), previously associated with other morphological transitions, which promote GUT cell formation. Together these studies help to understand how C. albicans’ phenotypic plasticity influences its interactions with the mammalian host.