Glycogen Metabolism in Candida albicans Impacts Fitness and Virulence during Vulvovaginal and Invasive Candidiasis

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.