The hyphal-specific toxin candidalysin promotes fungal gut commensalism

Shen-Huan Liang, Shabnam Sircaik, Joseph Dainis, Pallavi Kakade, Swathi Penumutchu, Liam D. McDonough, Ying-Han Chen, Corey Frazer, Tim B. Schille, Stefanie Allert, Osama Elshafee, Maria Hänel, Selene Mogavero, Shipra Vaishnava, Ken Cadwell, Peter Belenky, J. Christian Perez, Bernhard Hube (), Iuliana V. Ene and Richard J. Bennett ()
Additional contact information
Shen-Huan Liang: Brown University
Shabnam Sircaik: Brown University
Joseph Dainis: Brown University
Pallavi Kakade: Brown University
Swathi Penumutchu: Brown University
Liam D. McDonough: Brown University
Ying-Han Chen: University of Pennsylvania Perelman School of Medicine
Corey Frazer: Brown University
Tim B. Schille: Leibniz Institute for Natural Product Research and Infection Biology–Hans Knoell Institute (HKI)
Stefanie Allert: Leibniz Institute for Natural Product Research and Infection Biology–Hans Knoell Institute (HKI)
Osama Elshafee: Leibniz Institute for Natural Product Research and Infection Biology–Hans Knoell Institute (HKI)
Maria Hänel: Leibniz Institute for Natural Product Research and Infection Biology–Hans Knoell Institute (HKI)
Selene Mogavero: Leibniz Institute for Natural Product Research and Infection Biology–Hans Knoell Institute (HKI)
Shipra Vaishnava: Brown University
Ken Cadwell: University of Pennsylvania Perelman School of Medicine
Peter Belenky: Brown University
J. Christian Perez: The University of Texas Health Science Center at Houston
Bernhard Hube: Leibniz Institute for Natural Product Research and Infection Biology–Hans Knoell Institute (HKI)
Iuliana V. Ene: Université Paris Cité, Fungal Heterogeneity Group
Richard J. Bennett: Brown University

Nature, 2024, vol. 627, issue 8004, 620-627

Abstract: Abstract The fungus Candida albicans frequently colonizes the human gastrointestinal tract, from which it can disseminate to cause systemic disease. This polymorphic species can transition between growing as single-celled yeast and as multicellular hyphae to adapt to its environment. The current dogma of C. albicans commensalism is that the yeast form is optimal for gut colonization, whereas hyphal cells are detrimental to colonization but critical for virulence1–3. Here, we reveal that this paradigm does not apply to multi-kingdom communities in which a complex interplay between fungal morphology and bacteria dictates C. albicans fitness. Thus, whereas yeast-locked cells outcompete wild-type cells when gut bacteria are absent or depleted by antibiotics, hyphae-competent wild-type cells outcompete yeast-locked cells in hosts with replete bacterial populations. This increased fitness of wild-type cells involves the production of hyphal-specific factors including the toxin candidalysin4,5, which promotes the establishment of colonization. At later time points, adaptive immunity is engaged, and intestinal immunoglobulin A preferentially selects against hyphal cells1,6. Hyphal morphotypes are thus under both positive and negative selective pressures in the gut. Our study further shows that candidalysin has a direct inhibitory effect on bacterial species, including limiting their metabolic output. We therefore propose that C. albicans has evolved hyphal-specific factors, including candidalysin, to better compete with bacterial species in the intestinal niche.

Date: 2024
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DOI: 10.1038/s41586-024-07142-4

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