Rapid proliferation due to better metabolic adaptation results in full virulence of a filament-deficient Candida albicans strain

Christine Dunker, Melanie Polke, Bianca Schulze-Richter, Katja Schubert, Sven Rudolphi, A. Elisabeth Gressler, Tony Pawlik, Juan P. Prada Salcedo, M. Joanna Niemiec, Silvia Slesiona-Künzel, Marc Swidergall, Ronny Martin, Thomas Dandekar and Ilse D. Jacobsen ()
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Christine Dunker: Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute
Melanie Polke: Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute
Bianca Schulze-Richter: Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute
Katja Schubert: Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute
Sven Rudolphi: Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute
A. Elisabeth Gressler: Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute
Tony Pawlik: Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute
Juan P. Prada Salcedo: University of Würzburg
M. Joanna Niemiec: Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute
Silvia Slesiona-Künzel: Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute
Marc Swidergall: David Geffen School of Medicine at UCLA
Ronny Martin: University of Würzburg
Thomas Dandekar: University of Würzburg
Ilse D. Jacobsen: Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract The ability of the fungal pathogen Candida albicans to undergo a yeast-to-hypha transition is believed to be a key virulence factor, as filaments mediate tissue damage. Here, we show that virulence is not necessarily reduced in filament-deficient strains, and the results depend on the infection model used. We generate a filament-deficient strain by deletion or repression of EED1 (known to be required for maintenance of hyphal growth). Consistent with previous studies, the strain is attenuated in damaging epithelial cells and macrophages in vitro and in a mouse model of intraperitoneal infection. However, in a mouse model of systemic infection, the strain is as virulent as the wild type when mice are challenged with intermediate infectious doses, and even more virulent when using low infectious doses. Retained virulence is associated with rapid yeast proliferation, likely the result of metabolic adaptation and improved fitness, leading to high organ fungal loads. Analyses of cytokine responses in vitro and in vivo, as well as systemic infections in immunosuppressed mice, suggest that differences in immunopathology contribute to some extent to retained virulence of the filament-deficient mutant. Our findings challenge the long-standing hypothesis that hyphae are essential for pathogenesis of systemic candidiasis by C. albicans.

Date: 2021
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DOI: 10.1038/s41467-021-24095-8

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