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The fungal pathogen Candida albicans autoinduces hyphal morphogenesis by raising extracellular pH.

Vylkova S, Carman AJ, Danhof HA, Collette JR, Zhou H, Lorenz MC - MBio (2011)

Bottom Line: Under acidic conditions, this species can raise the pH from 4 to >7 in less than 12 h, resulting in autoinduction of the yeast-hyphal transition, a critical virulence trait.The pH changes are the result of the extrusion of ammonia, as observed in other fungi.This phenomenon is unprecedented in a human pathogen and may substantially impact host physiology by linking morphogenesis, pH adaptation, carbon metabolism, and interactions with host cells, all of which are critical for the ability of C. albicans to cause disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center, Houston, Texas, USA.

ABSTRACT

Unlabelled: pH homeostasis is critical for all organisms; in the fungal pathogen Candida albicans, pH adaptation is critical for virulence in distinct host niches. We demonstrate that beyond adaptation, C. albicans actively neutralizes the environment from either acidic or alkaline pHs. Under acidic conditions, this species can raise the pH from 4 to >7 in less than 12 h, resulting in autoinduction of the yeast-hyphal transition, a critical virulence trait. Extracellular alkalinization has been reported to occur in several fungal species, but under the specific conditions that we describe, the phenomenon is more rapid than previously observed. Alkalinization is linked to carbon deprivation, as it occurs in glucose-poor media and requires exogenous amino acids. These conditions are similar to those predicted to exist inside phagocytic cells, and we find a strong correlation between the use of amino acids as a cellular carbon source and the degree of alkalinization. Genetic and genomic approaches indicate an emphasis on amino acid uptake and catabolism in alkalinizing cells. Mutations in four genes, STP2, a transcription factor regulating amino acid permeases, ACH1 (acetyl-coenzyme A [acetyl-CoA] hydrolase), DUR1,2 (urea amidolyase), and ATO5, a putative ammonia transporter, abolish or delay neutralization. The pH changes are the result of the extrusion of ammonia, as observed in other fungi. We propose that nutrient-deprived C. albicans cells catabolize amino acids as a carbon source, excreting the amino nitrogen as ammonia to raise environmental pH and stimulate morphogenesis, thus directly contributing to pathogenesis.

Importance: Candida albicans is the most important fungal pathogen of humans, causing disease at multiple body sites. The ability to switch between multiple morphologies, including a rounded yeast cell and an elongated hyphal cell, is a key virulence trait in this species, as this reversible switch is thought to promote dissemination and tissue invasion in the host. We report here that C. albicans can actively alter the pH of its environment and induce its switch to the hyphal form. The change in pH is caused by the release of ammonia from the cells produced during the breakdown of amino acids. This phenomenon is unprecedented in a human pathogen and may substantially impact host physiology by linking morphogenesis, pH adaptation, carbon metabolism, and interactions with host cells, all of which are critical for the ability of C. albicans to cause disease.

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Related in: MedlinePlus

Model of environmental alkalinization by C. albicans. Under conditions in which amino acids are metabolized as carbon sources, the cell upregulates transmembrane transporters for various amino acids, facilitated by the Stp2p transcription factor. Amino acids are converted into tricarboxylic acid (TCA) cycle intermediates via several routes, many of which require acetyl-CoA production and intracellular transport mediated by acetyl-CoA hydrolase (Ach1p), and all of which remove the amine group(s). In mammals, excess nitrogen is excreted as urea, whereas we propose that in C. albicans this is converted into ammonia and CO2 by urea amidolyase (Dur1,2p) and exported from the cell in a process involving the Ato proteins.
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f7: Model of environmental alkalinization by C. albicans. Under conditions in which amino acids are metabolized as carbon sources, the cell upregulates transmembrane transporters for various amino acids, facilitated by the Stp2p transcription factor. Amino acids are converted into tricarboxylic acid (TCA) cycle intermediates via several routes, many of which require acetyl-CoA production and intracellular transport mediated by acetyl-CoA hydrolase (Ach1p), and all of which remove the amine group(s). In mammals, excess nitrogen is excreted as urea, whereas we propose that in C. albicans this is converted into ammonia and CO2 by urea amidolyase (Dur1,2p) and exported from the cell in a process involving the Ato proteins.

Mentions: Figure 7 presents a model for the metabolic functions that contribute to alkalinization, based on the utilization of amino acids as the primary source of carbon. Amino acid uptake via transmembrane permeases is required, and while there is significant redundancy in permease specificity, a deletion of the Stp2p transcription factor reduces expression of multiple permeases (34), and this ablates alkalinization. The close correlation of pH changes and growth indicates that catabolism of these amino acids is required. Amino acids are catabolized through several different routes, resulting in acetyl-CoA, succinyl-CoA, α-ketoglutarate, or oxaloacetate, each of which involves deamination steps. Under carbon-rich conditions nitrogen is generally stored in the form of glutamate and glutamine, but the capacity for doing so when amino acids are needed as a carbon source is presumably limited. High cytosolic ammonia concentrations are toxic (49), and excretion of the excess ammonia would both detoxify the cytosol and raise the extracellular pH. The Ato family of proteins has been proposed to be ammonia exporters—the name comes from “ammonia transport outward” (29)—and we find that deletion of one of these genes, ATO5, slows alkalinization. The Ato family is significantly enlarged in C. albicans (10 members) and other alkalinizing species relative to species that alkalinze poorly. We note that the most pathogenic CUG Candida species (C. albicans, C. tropicalis, and C. parapsilosis) have large Ato families, reminiscent of the expansion of gene families for a number of virulence-related traits, particularly those on the cell surface or secreted, such as secreted aspartyl proteases, lipases, and phospholipases, and GPI-anchored cell wall proteins such as the ALS agglutinins (27).


The fungal pathogen Candida albicans autoinduces hyphal morphogenesis by raising extracellular pH.

Vylkova S, Carman AJ, Danhof HA, Collette JR, Zhou H, Lorenz MC - MBio (2011)

Model of environmental alkalinization by C. albicans. Under conditions in which amino acids are metabolized as carbon sources, the cell upregulates transmembrane transporters for various amino acids, facilitated by the Stp2p transcription factor. Amino acids are converted into tricarboxylic acid (TCA) cycle intermediates via several routes, many of which require acetyl-CoA production and intracellular transport mediated by acetyl-CoA hydrolase (Ach1p), and all of which remove the amine group(s). In mammals, excess nitrogen is excreted as urea, whereas we propose that in C. albicans this is converted into ammonia and CO2 by urea amidolyase (Dur1,2p) and exported from the cell in a process involving the Ato proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3101780&req=5

f7: Model of environmental alkalinization by C. albicans. Under conditions in which amino acids are metabolized as carbon sources, the cell upregulates transmembrane transporters for various amino acids, facilitated by the Stp2p transcription factor. Amino acids are converted into tricarboxylic acid (TCA) cycle intermediates via several routes, many of which require acetyl-CoA production and intracellular transport mediated by acetyl-CoA hydrolase (Ach1p), and all of which remove the amine group(s). In mammals, excess nitrogen is excreted as urea, whereas we propose that in C. albicans this is converted into ammonia and CO2 by urea amidolyase (Dur1,2p) and exported from the cell in a process involving the Ato proteins.
Mentions: Figure 7 presents a model for the metabolic functions that contribute to alkalinization, based on the utilization of amino acids as the primary source of carbon. Amino acid uptake via transmembrane permeases is required, and while there is significant redundancy in permease specificity, a deletion of the Stp2p transcription factor reduces expression of multiple permeases (34), and this ablates alkalinization. The close correlation of pH changes and growth indicates that catabolism of these amino acids is required. Amino acids are catabolized through several different routes, resulting in acetyl-CoA, succinyl-CoA, α-ketoglutarate, or oxaloacetate, each of which involves deamination steps. Under carbon-rich conditions nitrogen is generally stored in the form of glutamate and glutamine, but the capacity for doing so when amino acids are needed as a carbon source is presumably limited. High cytosolic ammonia concentrations are toxic (49), and excretion of the excess ammonia would both detoxify the cytosol and raise the extracellular pH. The Ato family of proteins has been proposed to be ammonia exporters—the name comes from “ammonia transport outward” (29)—and we find that deletion of one of these genes, ATO5, slows alkalinization. The Ato family is significantly enlarged in C. albicans (10 members) and other alkalinizing species relative to species that alkalinze poorly. We note that the most pathogenic CUG Candida species (C. albicans, C. tropicalis, and C. parapsilosis) have large Ato families, reminiscent of the expansion of gene families for a number of virulence-related traits, particularly those on the cell surface or secreted, such as secreted aspartyl proteases, lipases, and phospholipases, and GPI-anchored cell wall proteins such as the ALS agglutinins (27).

Bottom Line: Under acidic conditions, this species can raise the pH from 4 to >7 in less than 12 h, resulting in autoinduction of the yeast-hyphal transition, a critical virulence trait.The pH changes are the result of the extrusion of ammonia, as observed in other fungi.This phenomenon is unprecedented in a human pathogen and may substantially impact host physiology by linking morphogenesis, pH adaptation, carbon metabolism, and interactions with host cells, all of which are critical for the ability of C. albicans to cause disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center, Houston, Texas, USA.

ABSTRACT

Unlabelled: pH homeostasis is critical for all organisms; in the fungal pathogen Candida albicans, pH adaptation is critical for virulence in distinct host niches. We demonstrate that beyond adaptation, C. albicans actively neutralizes the environment from either acidic or alkaline pHs. Under acidic conditions, this species can raise the pH from 4 to >7 in less than 12 h, resulting in autoinduction of the yeast-hyphal transition, a critical virulence trait. Extracellular alkalinization has been reported to occur in several fungal species, but under the specific conditions that we describe, the phenomenon is more rapid than previously observed. Alkalinization is linked to carbon deprivation, as it occurs in glucose-poor media and requires exogenous amino acids. These conditions are similar to those predicted to exist inside phagocytic cells, and we find a strong correlation between the use of amino acids as a cellular carbon source and the degree of alkalinization. Genetic and genomic approaches indicate an emphasis on amino acid uptake and catabolism in alkalinizing cells. Mutations in four genes, STP2, a transcription factor regulating amino acid permeases, ACH1 (acetyl-coenzyme A [acetyl-CoA] hydrolase), DUR1,2 (urea amidolyase), and ATO5, a putative ammonia transporter, abolish or delay neutralization. The pH changes are the result of the extrusion of ammonia, as observed in other fungi. We propose that nutrient-deprived C. albicans cells catabolize amino acids as a carbon source, excreting the amino nitrogen as ammonia to raise environmental pH and stimulate morphogenesis, thus directly contributing to pathogenesis.

Importance: Candida albicans is the most important fungal pathogen of humans, causing disease at multiple body sites. The ability to switch between multiple morphologies, including a rounded yeast cell and an elongated hyphal cell, is a key virulence trait in this species, as this reversible switch is thought to promote dissemination and tissue invasion in the host. We report here that C. albicans can actively alter the pH of its environment and induce its switch to the hyphal form. The change in pH is caused by the release of ammonia from the cells produced during the breakdown of amino acids. This phenomenon is unprecedented in a human pathogen and may substantially impact host physiology by linking morphogenesis, pH adaptation, carbon metabolism, and interactions with host cells, all of which are critical for the ability of C. albicans to cause disease.

Show MeSH
Related in: MedlinePlus