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bioRxiv · 10.64898/2026.03.02.708673

Metabolic control of mitochondrial plasticity and extracellular vesicle biology drives Cryptococcus neoformans virulence

Fisher, M. C.·Hong, N.·Bai, X.·Yuan, H.·Yu, P.·Edwards, H.·Ma, Y.·Liao, W.·Chen, H.·Zheng, Q.·Wang, Y.·Wang, M.·Xu, J.·Chen, M.
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Abstract

Metabolic adaptation to nutrient stress is a key but poorly understood driver of fungal virulence. Here, we show that a dominant East Asian lineage of Cryptococcus neoformans (VNIa-5), which disproportionately infects immunocompetent hosts, has undergone lineage-specific rewiring of glucose-responsive stress pathways. Integrating population genomics, transcriptomics, and experimental infection models, we demonstrate that VNIa-5s clinical dominance is not explained by environmental prevalence. Instead, selective activation of Snf1 signalling links glucose limitation to mitochondrial tubularisation, extracellular vesicle remodelling, and enhanced melanization. Under low-glucose conditions, VNIa-5 exhibits marked mitochondrial plasticity and extracellular vesicle compositional shifts resembling hypervirulent outbreak lineages of Cryptococcus gattii. Following experimental induction of dormancy, VNIa-5 shows significantly increased virulence in vivo compared with the closely related but clinically rare VNIa-31 subclade, with host survival tightly correlated with mitochondrial morphology. These findings identify metabolic stress integration as a central mechanism shaping cryptococcal virulence and disease in immunocompetent human hosts.

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Fisher, M. C., Hong, N., Bai, X., Yuan, H., Yu, P., Edwards, H., Ma, Y., Liao, W., Chen, H., Zheng, Q., Wang, Y., Wang, M., Xu, J., Chen, M.. 2026-03-02. Metabolic control of mitochondrial plasticity and extracellular vesicle biology drives Cryptococcus neoformans virulence. https://doi.org/10.64898/2026.03.02.708673

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