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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.

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Opaque cells exhibit higher fitness, on average, at 25°C than at 37°C. (A) Phenotypic analysis of wild-type (WT), WOR1 overexpressing (WOR1 OE), and hgt4Δ opaque cells grown at 25°C or 37°C for 24 h in the presence of different N peptides (PM08). (B) Ratios of metabolic activities for opaque cells at the two temperatures were calculated for each strain for each condition. The 37°C/25°C metabolic activity ratios were sorted in ascending order to illustrate differences between strains. The averages of these ratios for each strain are also listed at the bottom of the figure. Asterisks denote significant differences (P < 0.05) relative to the value for the WT strain. (C) Ratios of WH/OP metabolic activities of wild-type and hgt4Δ cells grown at 37°C on N peptide sources (PM08). The WH/OP metabolic activity ratios were sorted in ascending order, and the averages of these ratios are listed. Asterisks denote significant differences relative to the WT strain (P < 0.05).
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fig7: Opaque cells exhibit higher fitness, on average, at 25°C than at 37°C. (A) Phenotypic analysis of wild-type (WT), WOR1 overexpressing (WOR1 OE), and hgt4Δ opaque cells grown at 25°C or 37°C for 24 h in the presence of different N peptides (PM08). (B) Ratios of metabolic activities for opaque cells at the two temperatures were calculated for each strain for each condition. The 37°C/25°C metabolic activity ratios were sorted in ascending order to illustrate differences between strains. The averages of these ratios for each strain are also listed at the bottom of the figure. Asterisks denote significant differences (P < 0.05) relative to the value for the WT strain. (C) Ratios of WH/OP metabolic activities of wild-type and hgt4Δ cells grown at 37°C on N peptide sources (PM08). The WH/OP metabolic activity ratios were sorted in ascending order, and the averages of these ratios are listed. Asterisks denote significant differences relative to the WT strain (P < 0.05).

Mentions: Opaque cells generally exhibited lower metabolic activity at 37°C than at 25°C (Fig. 2), and we examined whether this is a consequence of cells switching to the white state or whether opaque cells are truly wired for optimal fitness at the lower temperature. To test this, we increased opaque cell stability by overexpressing WOR1 (WOR1 OE strain [40, 42]) or by using the hgt4Δ mutant that displays increased opaque cell stability (see Fig. S6E in the supplemental material). Strains were grown for 24 h on different N and peptide sources (PM08 plate) and examined for metabolic activity, opaque cell stability, and filamentation. At 25°C, wild-type (WT), WOR1 OE, and hgt4Δ opaque cells were all mostly stable, although hgt4Δ cells displayed the highest levels of stability (Fig. 7A). At 37°C, WT and WOR1 OE opaque cells showed frequent switching to the white state, whereas hgt4Δ cells showed a broader distribution of cell types, with most cells retaining the opaque state (Fig. 7A).


Phenotypic Profiling Reveals that Candida albicans Opaque Cells Represent a Metabolically Specialized Cell State Compared to Default White Cells
Opaque cells exhibit higher fitness, on average, at 25°C than at 37°C. (A) Phenotypic analysis of wild-type (WT), WOR1 overexpressing (WOR1 OE), and hgt4Δ opaque cells grown at 25°C or 37°C for 24 h in the presence of different N peptides (PM08). (B) Ratios of metabolic activities for opaque cells at the two temperatures were calculated for each strain for each condition. The 37°C/25°C metabolic activity ratios were sorted in ascending order to illustrate differences between strains. The averages of these ratios for each strain are also listed at the bottom of the figure. Asterisks denote significant differences (P < 0.05) relative to the value for the WT strain. (C) Ratios of WH/OP metabolic activities of wild-type and hgt4Δ cells grown at 37°C on N peptide sources (PM08). The WH/OP metabolic activity ratios were sorted in ascending order, and the averages of these ratios are listed. Asterisks denote significant differences relative to the WT strain (P < 0.05).
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fig7: Opaque cells exhibit higher fitness, on average, at 25°C than at 37°C. (A) Phenotypic analysis of wild-type (WT), WOR1 overexpressing (WOR1 OE), and hgt4Δ opaque cells grown at 25°C or 37°C for 24 h in the presence of different N peptides (PM08). (B) Ratios of metabolic activities for opaque cells at the two temperatures were calculated for each strain for each condition. The 37°C/25°C metabolic activity ratios were sorted in ascending order to illustrate differences between strains. The averages of these ratios for each strain are also listed at the bottom of the figure. Asterisks denote significant differences (P < 0.05) relative to the value for the WT strain. (C) Ratios of WH/OP metabolic activities of wild-type and hgt4Δ cells grown at 37°C on N peptide sources (PM08). The WH/OP metabolic activity ratios were sorted in ascending order, and the averages of these ratios are listed. Asterisks denote significant differences relative to the WT strain (P < 0.05).
Mentions: Opaque cells generally exhibited lower metabolic activity at 37°C than at 25°C (Fig. 2), and we examined whether this is a consequence of cells switching to the white state or whether opaque cells are truly wired for optimal fitness at the lower temperature. To test this, we increased opaque cell stability by overexpressing WOR1 (WOR1 OE strain [40, 42]) or by using the hgt4Δ mutant that displays increased opaque cell stability (see Fig. S6E in the supplemental material). Strains were grown for 24 h on different N and peptide sources (PM08 plate) and examined for metabolic activity, opaque cell stability, and filamentation. At 25°C, wild-type (WT), WOR1 OE, and hgt4Δ opaque cells were all mostly stable, although hgt4Δ cells displayed the highest levels of stability (Fig. 7A). At 37°C, WT and WOR1 OE opaque cells showed frequent switching to the white state, whereas hgt4Δ cells showed a broader distribution of cell types, with most cells retaining the opaque state (Fig. 7A).

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&deg;C and 37&deg;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&deg;C, consistent with white cells being the default state of C.&nbsp;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&deg;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