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Phenotypic Profiling Reveals that Candida albicans Opaque Cells Represent a Metabolically Specialized Cell State Compared to Default White Cells

View Article: PubMed Central - PubMed

ABSTRACT

The 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.

No MeSH data available.


Related in: MedlinePlus

Filamentation of white and opaque cells is regulated by metabolic cues and temperature. (A) (Top) Percentage of white cells filamenting at 25°C and 37°C on different substrates. (Bottom) Percentage of opaque cells filamenting at 25°C and 37°C. (B) Overlap between conditions that induce >10% filamentation in white cells at 25°C and 37°C and between conditions that induce filamentation in opaque cells at 25°C and 37°C. Three conditions induced filamentation of both cell types at both temperatures. (C and D) Overlap between conditions that induce filamentation in white cells at 37°C and opaque cells at 25°C. Panel D highlights the divergent nutritional cues that induce filamentation at 37°C in white cells and at 25°C in opaque cells. For opaque cell filamentation data in panels A to D, only wells that contained >50% opaque cells at the end of the experiment were included.
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fig4: Filamentation of white and opaque cells is regulated by metabolic cues and temperature. (A) (Top) Percentage of white cells filamenting at 25°C and 37°C on different substrates. (Bottom) Percentage of opaque cells filamenting at 25°C and 37°C. (B) Overlap between conditions that induce >10% filamentation in white cells at 25°C and 37°C and between conditions that induce filamentation in opaque cells at 25°C and 37°C. Three conditions induced filamentation of both cell types at both temperatures. (C and D) Overlap between conditions that induce filamentation in white cells at 37°C and opaque cells at 25°C. Panel D highlights the divergent nutritional cues that induce filamentation at 37°C in white cells and at 25°C in opaque cells. For opaque cell filamentation data in panels A to D, only wells that contained >50% opaque cells at the end of the experiment were included.

Mentions: Approximately 14% of conditions induced white cell filamentation (i.e., >10% of the population grew as filamentous cells), resulting in the formation of pseudohyphae (chains of elongated cells with constrictions between cells) or true hyphae (long, polarized cells with no constrictions between cells). Filamentation-inducing conditions included different C sources, osmotic stress substrates (OS), and “chemicals” (Fig. 4A; see Fig. S2E and S2F and Table S1D in the supplemental material). Temperature was a particularly important factor influencing filamentation—353 conditions induced white cell filamentation at 37°C compared to only 56 conditions at 25°C (Fig. S2E). Several sugars (including glucose, fructose, maltose, etc.) represented the strongest inducers of true hyphae at 37°C (Table S1D). Stimuli that induced filamentation at both temperatures included GlcNAc (and GlcNAc variants), as well as several chemicals and arginine-containing peptides (Fig. 4B; Table S1D).


Phenotypic Profiling Reveals that Candida albicans Opaque Cells Represent a Metabolically Specialized Cell State Compared to Default White Cells
Filamentation of white and opaque cells is regulated by metabolic cues and temperature. (A) (Top) Percentage of white cells filamenting at 25°C and 37°C on different substrates. (Bottom) Percentage of opaque cells filamenting at 25°C and 37°C. (B) Overlap between conditions that induce >10% filamentation in white cells at 25°C and 37°C and between conditions that induce filamentation in opaque cells at 25°C and 37°C. Three conditions induced filamentation of both cell types at both temperatures. (C and D) Overlap between conditions that induce filamentation in white cells at 37°C and opaque cells at 25°C. Panel D highlights the divergent nutritional cues that induce filamentation at 37°C in white cells and at 25°C in opaque cells. For opaque cell filamentation data in panels A to D, only wells that contained >50% opaque cells at the end of the experiment were included.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig4: Filamentation of white and opaque cells is regulated by metabolic cues and temperature. (A) (Top) Percentage of white cells filamenting at 25°C and 37°C on different substrates. (Bottom) Percentage of opaque cells filamenting at 25°C and 37°C. (B) Overlap between conditions that induce >10% filamentation in white cells at 25°C and 37°C and between conditions that induce filamentation in opaque cells at 25°C and 37°C. Three conditions induced filamentation of both cell types at both temperatures. (C and D) Overlap between conditions that induce filamentation in white cells at 37°C and opaque cells at 25°C. Panel D highlights the divergent nutritional cues that induce filamentation at 37°C in white cells and at 25°C in opaque cells. For opaque cell filamentation data in panels A to D, only wells that contained >50% opaque cells at the end of the experiment were included.
Mentions: Approximately 14% of conditions induced white cell filamentation (i.e., >10% of the population grew as filamentous cells), resulting in the formation of pseudohyphae (chains of elongated cells with constrictions between cells) or true hyphae (long, polarized cells with no constrictions between cells). Filamentation-inducing conditions included different C sources, osmotic stress substrates (OS), and “chemicals” (Fig. 4A; see Fig. S2E and S2F and Table S1D in the supplemental material). Temperature was a particularly important factor influencing filamentation—353 conditions induced white cell filamentation at 37°C compared to only 56 conditions at 25°C (Fig. S2E). Several sugars (including glucose, fructose, maltose, etc.) represented the strongest inducers of true hyphae at 37°C (Table S1D). Stimuli that induced filamentation at both temperatures included GlcNAc (and GlcNAc variants), as well as several chemicals and arginine-containing peptides (Fig. 4B; Table S1D).

View Article: PubMed Central - PubMed

ABSTRACT

The 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.

No MeSH data available.


Related in: MedlinePlus