A gut-oral microbiome–driven axis controls oropharyngeal candidiasis through retinoic acid
Felix E.Y. Aggor, Martinna Bertolini, Chunsheng Zhou, Tiffany C. Taylor, Darryl A. Abbott, Javonn Musgrove, Vincent M. Bruno, Timothy W. Hand, Sarah L. Gaffen
Felix E.Y. Aggor, Martinna Bertolini, Chunsheng Zhou, Tiffany C. Taylor, Darryl A. Abbott, Javonn Musgrove, Vincent M. Bruno, Timothy W. Hand, Sarah L. Gaffen
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Research Article Immunology

A gut-oral microbiome–driven axis controls oropharyngeal candidiasis through retinoic acid

Abstract

A side effect of antibiotics is outgrowth of the opportunistic fungus Candida albicans in the oropharynx (oropharyngeal candidiasis, OPC). IL-17 signaling is vital for immunity to OPC, but how the microbiome impacts antifungal immunity is not well understood. Mice in standard specific pathogen–free (SPF) conditions are resistant to OPC, whereas we show that germ-free (GF) or antibiotic-treated mice are susceptible. Oral type 17 cells and IL-17–dependent responses were impaired in antibiotic-treated and GF mice. Susceptibility could be rescued in GF mice by mono-colonization with segmented filamentous bacterium (SFB), an intestine-specific constituent of the microbiota. SFB protection was accompanied by restoration of oral IL-17+CD4+ T cells and gene signatures characteristic of IL-17 signaling. Additionally, RNA-Seq revealed induction of genes in the retinoic acid (RA) and RA receptor–α (RARα) pathway. Administration of RA rescued immunity to OPC in microbiome-depleted or GF mice, while RAR inhibition caused susceptibility in immunocompetent animals. Surprisingly, immunity to OPC was independent of serum amyloids. Moreover, RAR inhibition did not alter oral type 17 cytokine levels. Thus, mono-colonization with a component of the intestinal microflora confers protection against OPC by type 17 and RA/RARα, which act in parallel to promote antifungal immunity. In principle, manipulation of the microbiome could be harnessed to maintain antifungal immunity.

Authors

Felix E.Y. Aggor, Martinna Bertolini, Chunsheng Zhou, Tiffany C. Taylor, Darryl A. Abbott, Javonn Musgrove, Vincent M. Bruno, Timothy W. Hand, Sarah L. Gaffen

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Figure 1

Microbiome depletion impairs type 17 responses in OPC.

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Microbiome depletion impairs type 17 responses in OPC. (A and B) WT mice...
(A and B) WT mice in SPF conditions (WT-SPF), ages 6–9 weeks, both sexes, were treated with or without antibiotics in drinking water for 7 days and infected orally by a 75-minute sublingual exposure to C. albicans or PBS (n = 9–12 mice/group). RNA from whole tongue prepared at day 2 p.i. was subjected to quantitative PCR (qPCR) for the indicated genes normalized to Gapdh. Graphs show mean ± SEM. Data are pooled from 2 independent experiments. Mice were infected and on day 2 p.i. tongue homogenates were analyzed by flow cytometry to assess (C) IL-17A production (CD4+IL17A+, gated on live CD45+ cells) and (D) neutrophils (CD11b+Ly6G+ gated on live CD45+ cells). (E) Mice were infected as in A, and on day 5 p.i. fungal burdens were assessed in tongue homogenates by plating and CFU enumeration. Graphs show geometric mean ± SD. Dashed line indicates limit of detection. Data were pooled from 2 independent experiments. (F) Mice treated as in A were administered recombinant IL-17A and IL-22 i.p. Fungal burdens were assessed at day 5. Dashed line indicates limit of detection. Data were pooled from 2 independent experiments. Data analyzed by ANOVA with Tukey’s multiple comparisons test (A–D) or Mann-Whitney U test (E and F). *P < 0.05, ** < 0.01, *** < 0.001, **** < 0.0001.