Abstract
ABSTRACTThe white-opaque switch is a bistable, epigenetic transition affecting multiple traits in Candida albicans including mating, immunogenicity, and niche specificity. To compare how the two cell states respond to external cues, we examined the fitness, phenotypic switching, and filamentation properties of white cells and opaque cells under 1,440 different conditions at 25°C and 37°C. We demonstrate that white and opaque cells display striking differences in their integration of metabolic and thermal cues, so that the two states exhibit optimal fitness under distinct conditions. White cells were fitter than opaque cells under a wide range of environmental conditions, including growth at various pHs and in the presence of chemical stresses or antifungal drugs. This difference was exacerbated at 37°C, consistent with white cells being the default state of C. albicans in the mammalian host. In contrast, opaque cells showed greater fitness than white cells under select nutritional conditions, including growth on diverse peptides at 25°C. We further demonstrate that filamentation is significantly rewired between the two states, with white and opaque cells undergoing filamentous growth in response to distinct external cues. Genetic analysis was used to identify signaling pathways impacting the white-opaque transition both in vitro and in a murine model of commensal colonization, and three sugar sensing pathways are revealed as regulators of the switch. Together, these findings establish that white and opaque cells are programmed for differential integration of metabolic and thermal cues and that opaque cells represent a more metabolically specialized cell state than the default white state.
Highlights
Many cells can undergo epigenetic, heritable transitions without changes in the primary DNA sequence, and such transitions are a key source of heterogeneity in the microbial world [1,2,3]
Our results reveal the following: (i) the metabolism of white and opaque cells is biased for optimal growth at different temperatures, with white cells generally fitter at 37°C than at 25°C, whereas the opposite is true for opaque cells; (ii) specific nutrients determine the effect of temperature on growth, with some nutrients supporting efficient growth at one temperature over the other independent of the phenotypic state of the cell
We provide an extensive analysis of the growth of white and opaque cells under various nutritional conditions at both 25°C and 37°C
Summary
Many cells can undergo epigenetic, heritable transitions without changes in the primary DNA sequence, and such transitions are a key source of heterogeneity in the microbial world [1,2,3] This type of heterogeneity is an effective strategy for microbes to deal with dynamic environments, where alternative cell states may be optimized for different conditions. C. albicans exists as a commensal species in humans, colonizing multiple mucosal surfaces of the body, but it is an opportunistic pathogen capable of causing life-threatening systemic infections [12] This species exhibits extensive phenotypic plasticity; it can grow as singlecelled yeast or multicellular hyphae, and can undergo epigenetic switching between alternative cell states. We sought to answer the following questions. (i) How does the fitness of white and opaque cells compare on different nutrients? (ii) How do environmental cues impact other phenotypes such as white-opaque switching and filamentation? (iii) What signaling pathways influence nutrient-induced white-opaque switching? (iv) how do thermal cues impact each of these traits? Our experiments establish that white and opaque states are wired differently for interactions with the environment—they are programmed to undergo optimal growth, filamentation, and biofilm formation on different nutrients and at different temperatures
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