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IL-17-mediated antifungal immunity restricts Candida albicans pathogenicity in the oral cavity

Nature Microbiology volume 11, pages 111–124 (2026)Cite this article

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Abstract

Candida albicans is a common resident of the microbiota that supports host homeostasis but can cause disease when immune defences are impaired. Mucocutaneous candidiasis in individuals with IL-17 immune defects provides insights into the immune system’s role in controlling C. albicans. Here, using a murine model of oral colonization, we show that IL-17 signalling maintains C. albicans in a non-pathogenic state. Loss of IL-17 leads to fungal filamentation and upregulation of hyphae-associated genes, which is accompanied by epithelial barrier disruption and inflammation, linked to aberrant IL-22 and IL-13 production. The emergence of pathogenic fungal traits was associated with impaired zinc chelation due to reduced calprotectin expression in the IL-17-deficient mice. Prolonged exposure to the immune-dysregulated tissue led to selection of stable, damage-inducing C. albicans variants, mirroring the evolution of isolates from a chronic mucocutaneous candidiasis patient. These findings reveal how IL-17 protects against fungal pathogenicity and how immune dysfunction fosters C. albicans adaptation and diversification within the host.

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Fig. 1: IL-17 deficiency interferes with C. albicans homeostatic colonization and is accompanied by local inflammation and pathology.
Fig. 2: IL-17 deficiency derepresses C. albicans pathogenic traits.
Fig. 3: The acquired fungal pathogenicity does not correlate with fungal overgrowth and is enhanced by dysregulated IL-22 production.
Fig. 4: IL-17 restricts C. albicans pathogenicity via the regulation of calprotectin.
Fig. 5: Host immune defects drive the evolution of pathogenic C. albicans strains in both mice and humans.

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Data availability

The data that support the findings of this study are publicly available via Zenodo at https://doi.org/10.5281/zenodo.17233074 ref. 90. RNA-seq datasets generated in this study are available at NCBI (GEO repository GSE280210).

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Acknowledgements

We thank the staff of the Laboratory Animal Service Center of the University of Zürich for animal husbandry; staff of the Laboratory for Animal Model Pathology of the University of Zürich for histology; the Functional Genomic Center of the University of Zürich for RNA-seq data acquisition and analysis; the Center for Clinical Studies (ZKS) of the University of Zürich for access to equipment; and members of the LeibundGut lab for helpful advice and discussions. This work was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie action, Innovative Training Network: FunHoMic (grant no. 812969 to S.L.-L. and C.d’E.), the Novartis Foundation for Medical-Biological Research (grant no. 22C224 to S.L.-L.), and a UZH Candoc grant (to R.F.-M.). Work in the laboratory of C.d’E. was supported by the Agence Nationale de Recherche (ANR-10-LABX-62-IBEID).

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Author notes

  1. These authors contributed equally: Kontxi Martinez de San Vicente, Corinne Maufrais.

Authors and Affiliations

  1. Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland

    Ricardo Fróis-Martins, Kontxi Martinez de San Vicente, Sarah Mertens & Salomé LeibundGut-Landmann

  2. Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland

    Ricardo Fróis-Martins, Kontxi Martinez de San Vicente, Sarah Mertens & Salomé LeibundGut-Landmann

  3. Institut Pasteur, Université Paris Cité, INRAE USC2019, Unité Biologie et Pathogénicité Fongiques, Paris, France

    Corinne Maufrais, Natacha Sertour, Emilie Sitterlé, Marie-Elisabeth Bougnoux & Christophe d’Enfert

  4. Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, Paris, France

    Corinne Maufrais

  5. Unité de Parasitologie-Mycologie, Service de Microbiologie Clinique, Hôpital Necker-Enfants-Malades, Assistance Publique des Hôpitaux de Paris (APHP), Paris, France

    Marie-Elisabeth Bougnoux

  6. Medical Research Council Centre for Medical Mycology at the University of Exeter, Department of Biosciences, Faculty of Health and Life Sciences, Exeter, UK

    Salomé LeibundGut-Landmann

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Contributions

R.F.-M. and S.L.-L. designed the study and wrote the paper. R.F.-M. performed the experiments and analysed the data. K.M.d.S.V. contributed to the experiments shown in Extended Data Fig. 4. S.M. conducted the experiment shown in Fig. 4a. C.M. and C.d’E. conducted the bioinformatic analyses. N.S., E.S., M.-E.B. and C.d’E. provided the C. albicans clinical isolates and related experimental data. S.M., N.S. and E.S. made equal contributions to the experimental work. S.L.-L. oversaw the study design and data analysis. R.F.-M., C.d’E. and S.L.-L. acquired the funding. All authors discussed the results and commented on the paper.

Corresponding author

Correspondence to Salomé LeibundGut-Landmann.

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Extended data

Extended Data Fig. 1 Dysregulated immune and tissue homeostasis in the tongue of C. albicans-colonized Il17rc−/− mice.

IL17rc−/− and heterozygous littermate control mice were associated with C. albicans strain 101 via sublingual administration. A. Body weight kinetics (n = 4 / group, mean ± SD). B. Heat map of differentially expressed cytokine genes on day 3 and 19 (n = 3 / group). C.–E. Quantification of the indicated transcripts in the colonized tongue on day 19 (n = 7 or 9 / group, mean ± SEM, data pooled from 3 independent experiments, except for Cxcl2 and Krt14 where n = 4, 5 or 6 / group, mean ± SEM, data pooled from 2 independent experiments. The grey shaded area represents the expression levels of each gene in naïve animals. The statistical significance of differences between groups was determined by Two-way ANOVA (A) while in (C–E) two-sided unpaired t-test was use in all genes analyzed except Krt10 which statistical significance was determined by Mann-Whitney test.

Extended Data Fig. 2 Flow cytometry analysis of immune cell populations in the C. albicans-colonized tongue and draining lymph nodes.

A. – B. Gating strategy for neutrophils, monocytes (A), and cytokine-producing T cells (B) in the C. albicans-colonized tongue on day 19. C. – D. Gating strategy (C) and quantification (D) of cytokine-producing T cells in the cervical lymph nodes on day 19. In D, each symbol represents an individual mouse; the mean ± SEM per group is indicated; n = 6 or 8/ group, pooled from 2 independent experiments. The statistical significance of differences between groups was determined by two-sided unpaired t-test (single-positive populations) or two-sided Mann-Whitney test (double-positive population).

Extended Data Fig. 3 Tissue pathology is sustained by the presence of C. albicans.

A. – B. IL17rc−/− and heterozygous littermate control mice were associated with C. albicans strain 101 for 75 days. PAS-stained tongue sections (A; representative of 4 mice / group from one independent experiment; Scale bars: 250 μm; 25 μm or 50 μm for the inserts) and quantification of the indicated transcripts in the colonized tongue (B, n = 4 / group, mean ± SD). The grey shaded area represents the expression levels of each gene in naïve animals. C. – E. IL17rc−/− and heterozygous littermate control mice associated with C. albicans strain 101 were treated with fluconazole from day 14 to the endpoint on day 19. Tongue CFUs (C), PAS-stained tongue sections (D; representative of 4 and 9 mice from 2 independent experiments; Scale bars: 250 μm; 25 μm or 50 μm for the inserts), and quantification of the indicated transcripts in the colonized tongue (E, n = 4 or 9 / group, mean ± SEM, data pooled from 2 independent experiments). F. – G. IL17rc−/− and heterozygous littermate control mice associated with C. albicans strain 101WT (50x reduced infection dose, l.d.) or 101ece1Δ/Δ for 19 days. Transcript levels of Krt10, Dsgl4 and Slurp2 in the colonized tongue (F, n = 4 or 5, mean ± SD) and PAS-stained tongue sections (G; representative of 10 and 12 mice / group from 3 independent experiments; Scale bars: 100 μm; 50 μm for the inserts). The grey shaded area represents the expression levels of each gene in naïve animals. The statistical significance of differences between groups was determined by two-sided unpaired t-test (B, E), or two-sided Mann-Whitney test (C). ns, not significant (p ≥ 0.05).

Extended Data Fig. 4 Characterization of the commensal C. albicans isolates CEC3672 and CEC3678.

A. Colony morphology on Spider agar. B. Quantification of the hyphal length after exposure of the indicated strains to TR146 oral keratinocytes for 3.5 h (n = 200 filaments / group for strains CEC3672 and CEC3678; n = 90 filaments / group for strains SC5314 and 101, mean ± SD). C. LDH release from TR146 oral keratinocytes after exposure to the indicated strains for 24 h (n = 16 / group, mean ± SEM, data pooled from two independent experiments). D. Quantification of IL-1α in the supernatant of TR146 oral keratinocytes after exposure to the indicated strains for 24 h (n = 6 / group, mean ± SD). E. CFUs in the tongue of wildtype mice that were colonized with CEC3672 or CEC3678 for 1, 6 or 30 days. Each symbol is the mean ± SEM per group (n = 3, 5 or 6 / group pooled from 2 independent experiments). F. PAS-stained tongue sections of wild-type mice that were colonized with CEC3672 or CEC3678 for 1 day (representative of 6 mice / group from 2 independent experiments). Scale bars: 100 μm. In B, C, and D, the statistical significance of differences between groups was determined by One-way ANOVA. ns, not significant (p ≥ 0.05).

Extended Data Fig. 5 The acquired fungal virulence is not explained by aberrant IFN-I, IFN-γ or IL-13 expression.

Il17rc−/− Ifnar−/−, Il17rc−/− Ifngr−/− or Il17rc−/− Il4ra−/− double knockout mice and the respective heterozygous littermate control mice (Il17rc−/−) were associated with C. albicans strain 101 for 19 days. A. Tongue CFUs (n = 7, 8 or 9 / group, mean ± SEM, data pooled from 2-3 independent experiments). B. PAS-stained tongue sections (representative of at least 7 mice / group from 2-3 independent experiments). Scale bars: 100 μm; 25 μm for the inserts. C.–H. Il22, Krt10, and Dsg4 host transcripts and ECE1, HWP1, and SAP5 fungal transcripts in the colonized tongue as indicated. n = 4, 5, 7, 8 or 9 / group, mean ± SEM, data pooled from 2-3 independent experiments (or, for some genes n = 3 from one representative experiment, mean ± SD). The grey shaded area represents the expression levels of each host gene in naïve animals. The statistical significance of differences between groups was determined by two-sided Mann-Whitney (A, left panel) or two-sided unpaired t-test (A, middle and right panels, and C–H). ns, not significant (p ≥ 0.05).

Extended Data Fig. 6 IL-17 restricts C. albicans pathogenicity via the regulation of calprotectin.

A. IL17rc−/− mice were associated with C. albicans strain 101 via sublingual administration and ECE1, HWP1, SAP5 fungal transcripts were evaluated on day 3, 7 and 19 (n = 3 or 4 / group, mean ± SD). B.–C. IL17rc−/− and heterozygous littermate control mice were associated with C. albicans strain 101. B. Krt10, Dsg4, Slurp1 and Dsg1 expression in the colonized tongue on day 7 and 14 (n = 4 or 5 / group, mean ± SEM, data pooled from 2 independent experiments). The grey shaded area represents the expression levels of each gene in naïve animals. C. PAS-stained tongue tissue sections on day 7 (representative of 4 mice / group from 2 independent experiments; scale bars: 50 μm). D.–E. IL17rc−/− and heterozygous littermate control mice naïve mice PAS-stained tongue sections (D; representative of 5 mice / group from 2 independent experiments), expression of epithelial structural genes (E, n = 5 / group, mean ± SEM, data pooled from 2 independent experiments). F. Heat map of differentially expressed AMP genes in the tongue of IL17rc−/− and heterozygous littermate control mice on day 3 and day 19 (n = 3 / group). G. PRA1 expression by strain 101 upon exposure to recombinant calprotectin for 3.5-4 h (n = 4 / group, mean ± SEM, data pooled from 2 independent experiments). H. Representative images of C. albicans strains CEC3672 and CEC3678 in F12 medium for 3.5 - 4 h. I.–J. Filamentation of C. albicans strains CEC3672 and CEC3678 when put in contact with IMOK cells and supplemented with TPEN and ZnSO4, as indicated. Representative images (I) and quantification of hyphae length and IMOK cell invasion (J) after 3.5 - 4 h of exposure. Each symbol represents a hyphae filament (J, left panel; quantification of > 60 fungal cells / group, mean ± SD) or the percentage of hyphae invasion per analyzed image (J, right panel; n = 5 / group, mean ± SD). The statistical significance of differences between groups was determined by Two-way ANOVA (B), two-sided Mann-Whitney test (G), Kruskal-Wallis test (F left panel) or One-way ANOVA (A and F right panel). ns, not significant (p ≥ 0.05).

Extended Data Fig. 7 Phylogenetic tree for C. albicans strains used in this study.

Tree representing the phylogenetic relationships between 182 isolates representative of the C. albicans population, strain 101 and two mouse-evolved isolates derived from strain 101, namely Evo1 and Evo2 (shown in green) and strains CEC4511, CEC4512, CEC4513 and CEC4514 from a CMC patient (shown in red). The tree illustrates the phylogenetic proximity of strains 101, Evo1 and Evo2 suggesting that these 3 strains share a common ancestor and that strains Evo1 and Evo2 are likely derived from strain 101. It also illustrates the phylogenetic proximity of strains CEC4511, CEC4512, CEC4513 and CEC4514 suggesting that these 4 strains share a common ancestor and are likely derived one from another.

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Fróis-Martins, R., Martinez de San Vicente, K., Maufrais, C. et al. IL-17-mediated antifungal immunity restricts Candida albicans pathogenicity in the oral cavity. Nat Microbiol 11, 111–124 (2026). https://doi.org/10.1038/s41564-025-02198-y

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