Host albumin redirects Candida albicans metabolism to engage an alternative pathogenicity pathway

Sophia U. J. Hitzler, Candela Fernández-Fernández, Kerstin Günther, Axel Dietschmann, Hrant Hovhannisyan, Anna Möslinger, Sophie Austermeier, Beatriz Cristóvão, Gianluca Vascelli, Teresa Zelante, Marina Pekmezović, Bernardo Ramírez-Zavala, Joachim Morschhäuser, Oliver Werz, Toni Gabaldón, Paul M. Jordan, Slavena Vylkova and Mark S. Gresnigt ()
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Sophia U. J. Hitzler: Leibniz Institute for Natural Product Research and Infection Biology—Hans-Knöll-Institute (Leibniz-HKI)
Candela Fernández-Fernández: Leibniz Institute for Natural Product Research and Infection Biology—Hans-Knöll-Institute (Leibniz-HKI)
Kerstin Günther: Friedrich Schiller University
Axel Dietschmann: Leibniz Institute for Natural Product Research and Infection Biology—Hans-Knöll-Institute (Leibniz-HKI)
Hrant Hovhannisyan: Barcelona Supercomputing Center (BSC-CNS)
Anna Möslinger: Leibniz-HKI
Sophie Austermeier: Leibniz-HKI
Beatriz Cristóvão: Leibniz Institute for Natural Product Research and Infection Biology—Hans-Knöll-Institute (Leibniz-HKI)
Gianluca Vascelli: University of Perugia
Teresa Zelante: University of Perugia
Marina Pekmezović: Leibniz Institute for Natural Product Research and Infection Biology—Hans-Knöll-Institute (Leibniz-HKI)
Bernardo Ramírez-Zavala: University of Würzburg
Joachim Morschhäuser: University of Würzburg
Oliver Werz: Friedrich Schiller University
Toni Gabaldón: Barcelona Supercomputing Center (BSC-CNS)
Paul M. Jordan: Friedrich Schiller University
Slavena Vylkova: Hans Knöll Institute
Mark S. Gresnigt: Leibniz Institute for Natural Product Research and Infection Biology—Hans-Knöll-Institute (Leibniz-HKI)

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Pathogenicity mechanisms of the yeast Candida albicans involve filamentous growth, adhesion, invasion, and toxin production. Interestingly, clinical isolates, and other Candida spp., can cause infection independent of filamentation or toxin production. These strains and species often are characterized as avirulent ex vivo, yet this does not correlate with their potential to cause infection. We hypothesized that specific host factors, which trigger pathogenicity in vivo, are absent in in vitro infection models and thereby clinical isolates can seem avirulent ex vivo. We investigated how albumin, the most abundant protein in humans, impacts infection and cytotoxic potential of C. albicans in vitro. The presence of albumin induces otherwise non-damaging and non-filamentous clinical isolates to cause host cell cytotoxicity. Moreover, avirulent deletion mutants deficient in filamentation, adhesion, or toxin production are restored in their cytotoxicity by albumin. This involves transcriptional and metabolic reprogramming of C. albicans, increasing biofilm formation and production of the oxylipin 13-hydroxyoctadecadienoic acid, driving host cell cytotoxicity. Collectively, our study uncoveres a pathogenicity mechanism by which C. albicans causes epithelial cytotoxicity independent of its conventional virulence mechanisms. This alternative pathogenicity strategy helps to explain the avirulence of clinical isolates ex vivo, when they are separated from the host environment.

Date: 2025
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DOI: 10.1038/s41467-025-61701-5

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