Host albumin redirects Candida albicans metabolism to engage an alternative pathogenicity pathway
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.
Authors
- Marina Pekmezović (ORCID: https://orcid.org/0000-0003-1991-9634)
- Toni Gabaldón (ORCID: https://orcid.org/0000-0003-0019-1735)
- Bernardo Ramı́rez-Zavala (ORCID: https://orcid.org/0000-0002-8063-9255)
- Mark S. Gresnigt (ORCID: https://orcid.org/0000-0002-9514-4634)
- Paul M. Jordan (ORCID: https://orcid.org/0000-0002-8364-4236)
- Slavena Vylkova
- Joachim Morschhäuser (ORCID: https://orcid.org/0000-0003-4227-8687)
- Sophie Austermeier (ORCID: https://orcid.org/0000-0002-1048-5983)
- Oliver Werz (ORCID: https://orcid.org/0000-0002-5064-4379)
- Beatriz Cristóvão
- Hrant Hovhannisyan (ORCID: https://orcid.org/0000-0003-2627-8505)
- Teresa Zelante (ORCID: https://orcid.org/0000-0002-7071-0302)
- Sophia U J Hitzler (ORCID: https://orcid.org/0000-0002-3582-2544)
- K Günther (ORCID: https://orcid.org/0000-0001-8230-5972)
- Axel Dietschmann (ORCID: https://orcid.org/0000-0002-0598-9714)
- Gianluca Vascelli
- Anna Möslinger
- Candela Fernández-Fernández (ORCID: https://orcid.org/0000-0002-3277-7522)
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- University of California, San Francisco (US)
- University of Würzburg (DE)
- University of Perugia (IT)
- Barcelona Supercomputing Center (ES)
- Leibniz Association (DE)
- Centro de Investigación Biomédica en Red (ES)
- Institute for Research in Biomedicine (ES)
- UCSF Benioff Children's Hospital (US)
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
- Anaxomics (Spain) (ES)
- Friedrich Schiller University Jena (DE)
- Universitat Politècnica de Catalunya (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-12
- DOI
- https://doi.org/10.1038/s41467-025-61701-5
- Citations
- 5
- Primary Topic
- Antifungal resistance and susceptibility
- Type
- article
- Field-Weighted Citation Impact
- 6.98
Funders
- Carl-Zeiss-Stiftung
- Institute for Research in Biomedicine
- Friedrich-Schiller-Universität Jena
- Freistaat Thüringen
- European Commission
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Institució Catalana de Recerca i Estudis Avançats
- KU Leuven
- Radboud Universitair Medisch Centrum
- Barcelona Supercomputing Center
- Universität Zürich
- Boehringer Ingelheim Stiftung
- Julius-Maximilians-Universität Würzburg
- Università degli Studi di Perugia
- Leibniz-Gemeinschaft
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie – Hans-Knöll-Institut