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Abstract Studying fungal virulence is often challenging and frequently depends on many contexts, including host immune status and pathogen genetic background. However, the role of ploidy has often been overlooked when studying virulence in eukaryotic pathogens. Since fungal pathogens, including the human opportunistic pathogenCandida albicans, can display extensive ploidy variation, assessing how ploidy impacts virulence has important clinical relevance. As an opportunistic pathogen,C. albicanscauses nonlethal, superficial infections in healthy individuals, but life‐threatening bloodstream infections in individuals with compromised immune function. Here, we determined how both ploidy and genetic background ofC. albicansimpacts virulence phenotypes in healthy and immunocompromised nematode hosts by characterizing virulence phenotypes in four near‐isogenic diploid and tetraploid pairs of strains, which included both laboratory and clinical genetic backgrounds. We found thatC. albicansinfections decreased host survival and negatively impacted host reproduction, and we leveraged these two measures to survey both lethal and nonlethal virulence phenotypes across the multipleC. albicansstrains. In this study, we found that regardless of pathogen ploidy or genetic background, immunocompromised hosts were susceptible to fungal infection compared to healthy hosts. Furthermore, for each host context, we found a significant interaction betweenC. albicansgenetic background and ploidy on virulence phenotypes, but no global differences between diploid and tetraploid pathogens were observed.
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Glycerophosphocholine provision rescues Candida albicans growth and signaling phenotypes associated with phosphate limitation
ABSTRACT The fungal pathogenCandida albicansmust acquire phosphate to colonize, infect, and proliferate in the human host.C. albicanshas four inorganic phosphate (Pi) transporters, Pho84 being the major high-affinity transporter; its cells can also use glycerophosphocholine (GPC) as their sole phosphate source. GPC is a lipid metabolite derived from deacylation of the lipid phosphatidylcholine. GPC is found in multiple human tissues, including the renal medulla, where it acts as an osmolyte.C. albicansimports GPC into the cell via the Git3 and Git4 transporters. Internalized GPC can be hydrolyzed to release Pi. To determine if GPC import and subsequent metabolism affect phosphate homeostasis upon Pilimitation, we monitored growth and phenotypic outputs in cells provided with either Pior GPC. Inpho84∆/∆ mutant cells that exhibit phenotypes associated with Pilimitation, GPC provision rescued sensitivity to osmotic and cell wall stresses. The glycerophosphodiesterase Gde1 was required for phenotypic rescue of osmotic stress by GPC provision. GPC provision, like Piprovision, resulted in repression of the PHO regulon and activation of TORC1 signaling. Piuptake was similar to GPC uptake when phosphate availability was low (200 µM). While available at lower concentrations than Piin the human host, GPC is an advantageous Pisource for the fungus because it simultaneously serves as a choline source. In summary, we find GPC is capable of substituting for PiinC. albicansby many though not all criteria and may contribute to phosphate availability for the fungus in the human host. IMPORTANCECandida albicansis the most commonly isolated species from patients suffering from invasive fungal disease.C. albicansis most commonly a commensal organism colonizing a variety of niches in the human host. The fungus must compete for resources with the host flora to acquire essential nutrients such as phosphate. Phosphate acquisition and homeostasis have been shown to play a key role inC. albicansvirulence, with several genes involved in these processes being required for normal virulence and several being upregulated during infection. In addition to inorganic phosphate (Pi),C. albicanscan utilize the lipid-derived metabolite glycerophosphocholine (GPC) as a phosphate source. As GPC is available within the human host, we examined the role of GPC in phosphate homeostasis inC. albicans. We find that GPC can substitute for Piby many though not all criteria and is likely a relevant physiological phosphate source forC. albicans.
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- Award ID(s):
- 1757555
- PAR ID:
- 10502935
- Editor(s):
- Lorenz, Michael
- Publisher / Repository:
- mSphere Open Access
- Date Published:
- Journal Name:
- mSphere
- Edition / Version:
- 1
- Volume:
- 8
- Issue:
- 6
- ISSN:
- 2379-5042
- Page Range / eLocation ID:
- na
- Subject(s) / Keyword(s):
- phosphate metabolism, phospholipids, Candida albicans, glycerophosphodiesters, phosphate, cell signaling
- Format(s):
- Medium: X Size: 961 KB Other: pdf
- Size(s):
- 961 KB
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1128/msphere.00231-23
