Glycogen Metabolism in Candida albicans Impacts Fitness and Virulence during Vulvovaginal and Invasive Candidiasis
ABSTRACT The polymorphic fungus Candida albicans remains a leading cause of both invasive and superficial mycoses, including vulvovaginal candidiasis (VVC). Metabolic plasticity, including carbohydrate catabolism, confers fitness advantages at anatomical site-specific host niches. C. albicans posses...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2023-04-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00046-23 |
| _version_ | 1797839587122348032 |
|---|---|
| author | Jian Miao Jessica Regan Chun Cai Glen E. Palmer David L. Williams Michael D. Kruppa Brian M. Peters |
| author_facet | Jian Miao Jessica Regan Chun Cai Glen E. Palmer David L. Williams Michael D. Kruppa Brian M. Peters |
| author_sort | Jian Miao |
| collection | DOAJ |
| description | ABSTRACT The polymorphic fungus Candida albicans remains a leading cause of both invasive and superficial mycoses, including vulvovaginal candidiasis (VVC). Metabolic plasticity, including carbohydrate catabolism, confers fitness advantages at anatomical site-specific host niches. C. albicans possesses the capacity to accumulate and store carbohydrates as glycogen and can consume intracellular glycogen stores when nutrients become limited. In the vaginal environment, estrogen promotes epithelial glycogen accumulation and C. albicans colonization. However, whether these factors are mechanistically linked is unexplored. Here, we characterized the glycogen metabolism pathways in C. albicans and investigated whether these impact the long-term survival of C. albicans, both in vitro and in vivo during murine VVC, or virulence during systemic infection. SC5314 and 6 clinical isolates demonstrated impaired growth when glycogen was used as the sole carbon source, suggesting that environmental glycogen acquisition is limited. The genetic deletion and complementation of key genes involved in glycogen metabolism in Saccharomyces cerevisiae confirmed that GSY1 and GLC3, as well as GPH1 and GDB1, are essential for glycogen synthesis and catabolism in C. albicans, respectively. Potential compensatory roles for a glucoamylase encoded by SGA1 were also explored. Competitive survival assays revealed that gsy1Δ/Δ, gph1Δ/Δ, and gph1Δ/Δ sga1Δ/Δ mutants exhibited long-term survival defects in vitro under starvation conditions and in vivo during vaginal colonization. A complete inability to catabolize glycogen (gph1Δ/Δ sga1Δ/Δ) also rendered C. albicans significantly less virulent during disseminated infections. This is the first study fully validating the glycogen metabolism pathways in C. albicans, and the results further suggest that intracellular glycogen catabolism positively impacts the long-term fitness of C. albicans in nutrient deficient environments and is important for full virulence. IMPORTANCE Glycogen is a highly branched polymer of glucose and is used across the tree of life as an efficient and compact form of energy storage. Whereas glycogen metabolism pathways have been studied in model yeasts, they have not been extensively explored in pathogenic fungi. Using a combination of microbiologic, molecular genetic, and biochemical approaches, we reveal orthologous functions of glycogen metabolism genes in the fungal pathogen Candida albicans. We also provide evidence that extracellular glycogen poorly supports growth across the Candida species and clinical isolates. Competitive fitness assays reveal that the loss of glycogen synthesis or catabolism significantly impacts survival during both in vitro starvation and the colonization of the mouse vagina. Moreover, a global glycogen catabolism mutant is rendered less virulent during murine invasive candidiasis. Therefore, this work demonstrates that glycogen metabolism in C. albicans contributes to survival and virulence in the mammalian host and may be a novel antifungal target. |
| first_indexed | 2024-04-09T16:00:23Z |
| format | Article |
| id | doaj.art-1de41200d62b4cc183dadf2e409c26eb |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-09T16:00:23Z |
| publishDate | 2023-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-1de41200d62b4cc183dadf2e409c26eb2023-04-25T13:04:57ZengAmerican Society for MicrobiologymBio2150-75112023-04-0114210.1128/mbio.00046-23Glycogen Metabolism in Candida albicans Impacts Fitness and Virulence during Vulvovaginal and Invasive CandidiasisJian Miao0Jessica Regan1Chun Cai2Glen E. Palmer3David L. Williams4Michael D. Kruppa5Brian M. Peters6Pharmaceutical Sciences Program, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USAPharmaceutical Sciences Program, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USADepartment of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USADepartment of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USADepartment of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USACenter of Excellence in Inflammation, Infectious Disease, and Immunity, East Tennessee State University, Johnson City, Tennessee, USADepartment of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USAABSTRACT The polymorphic fungus Candida albicans remains a leading cause of both invasive and superficial mycoses, including vulvovaginal candidiasis (VVC). Metabolic plasticity, including carbohydrate catabolism, confers fitness advantages at anatomical site-specific host niches. C. albicans possesses the capacity to accumulate and store carbohydrates as glycogen and can consume intracellular glycogen stores when nutrients become limited. In the vaginal environment, estrogen promotes epithelial glycogen accumulation and C. albicans colonization. However, whether these factors are mechanistically linked is unexplored. Here, we characterized the glycogen metabolism pathways in C. albicans and investigated whether these impact the long-term survival of C. albicans, both in vitro and in vivo during murine VVC, or virulence during systemic infection. SC5314 and 6 clinical isolates demonstrated impaired growth when glycogen was used as the sole carbon source, suggesting that environmental glycogen acquisition is limited. The genetic deletion and complementation of key genes involved in glycogen metabolism in Saccharomyces cerevisiae confirmed that GSY1 and GLC3, as well as GPH1 and GDB1, are essential for glycogen synthesis and catabolism in C. albicans, respectively. Potential compensatory roles for a glucoamylase encoded by SGA1 were also explored. Competitive survival assays revealed that gsy1Δ/Δ, gph1Δ/Δ, and gph1Δ/Δ sga1Δ/Δ mutants exhibited long-term survival defects in vitro under starvation conditions and in vivo during vaginal colonization. A complete inability to catabolize glycogen (gph1Δ/Δ sga1Δ/Δ) also rendered C. albicans significantly less virulent during disseminated infections. This is the first study fully validating the glycogen metabolism pathways in C. albicans, and the results further suggest that intracellular glycogen catabolism positively impacts the long-term fitness of C. albicans in nutrient deficient environments and is important for full virulence. IMPORTANCE Glycogen is a highly branched polymer of glucose and is used across the tree of life as an efficient and compact form of energy storage. Whereas glycogen metabolism pathways have been studied in model yeasts, they have not been extensively explored in pathogenic fungi. Using a combination of microbiologic, molecular genetic, and biochemical approaches, we reveal orthologous functions of glycogen metabolism genes in the fungal pathogen Candida albicans. We also provide evidence that extracellular glycogen poorly supports growth across the Candida species and clinical isolates. Competitive fitness assays reveal that the loss of glycogen synthesis or catabolism significantly impacts survival during both in vitro starvation and the colonization of the mouse vagina. Moreover, a global glycogen catabolism mutant is rendered less virulent during murine invasive candidiasis. Therefore, this work demonstrates that glycogen metabolism in C. albicans contributes to survival and virulence in the mammalian host and may be a novel antifungal target.https://journals.asm.org/doi/10.1128/mbio.00046-23Candida albicansglycogenmetabolismvulvovaginalcandidiasisCandida |
| spellingShingle | Jian Miao Jessica Regan Chun Cai Glen E. Palmer David L. Williams Michael D. Kruppa Brian M. Peters Glycogen Metabolism in Candida albicans Impacts Fitness and Virulence during Vulvovaginal and Invasive Candidiasis mBio Candida albicans glycogen metabolism vulvovaginal candidiasis Candida |
| title | Glycogen Metabolism in Candida albicans Impacts Fitness and Virulence during Vulvovaginal and Invasive Candidiasis |
| title_full | Glycogen Metabolism in Candida albicans Impacts Fitness and Virulence during Vulvovaginal and Invasive Candidiasis |
| title_fullStr | Glycogen Metabolism in Candida albicans Impacts Fitness and Virulence during Vulvovaginal and Invasive Candidiasis |
| title_full_unstemmed | Glycogen Metabolism in Candida albicans Impacts Fitness and Virulence during Vulvovaginal and Invasive Candidiasis |
| title_short | Glycogen Metabolism in Candida albicans Impacts Fitness and Virulence during Vulvovaginal and Invasive Candidiasis |
| title_sort | glycogen metabolism in candida albicans impacts fitness and virulence during vulvovaginal and invasive candidiasis |
| topic | Candida albicans glycogen metabolism vulvovaginal candidiasis Candida |
| url | https://journals.asm.org/doi/10.1128/mbio.00046-23 |
| work_keys_str_mv | AT jianmiao glycogenmetabolismincandidaalbicansimpactsfitnessandvirulenceduringvulvovaginalandinvasivecandidiasis AT jessicaregan glycogenmetabolismincandidaalbicansimpactsfitnessandvirulenceduringvulvovaginalandinvasivecandidiasis AT chuncai glycogenmetabolismincandidaalbicansimpactsfitnessandvirulenceduringvulvovaginalandinvasivecandidiasis AT glenepalmer glycogenmetabolismincandidaalbicansimpactsfitnessandvirulenceduringvulvovaginalandinvasivecandidiasis AT davidlwilliams glycogenmetabolismincandidaalbicansimpactsfitnessandvirulenceduringvulvovaginalandinvasivecandidiasis AT michaeldkruppa glycogenmetabolismincandidaalbicansimpactsfitnessandvirulenceduringvulvovaginalandinvasivecandidiasis AT brianmpeters glycogenmetabolismincandidaalbicansimpactsfitnessandvirulenceduringvulvovaginalandinvasivecandidiasis |