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Activation of HIF-1α and LL-37 by commensal bacteria inhibits Candida albicans colonization

Abstract

Candida albicans colonization is required for invasive disease1,2,3. Unlike humans, adult mice with mature intact gut microbiota are resistant to C. albicans gastrointestinal (GI) colonization2,4, but the factors that promote C. albicans colonization resistance are unknown. Here we demonstrate that commensal anaerobic bacteria—specifically clostridial Firmicutes (clusters IV and XIVa) and Bacteroidetes—are critical for maintaining C. albicans colonization resistance in mice. Using Bacteroides thetaiotamicron as a model organism, we find that hypoxia-inducible factor-1α (HIF-1α), a transcription factor important for activating innate immune effectors, and the antimicrobial peptide LL-37 (CRAMP in mice) are key determinants of C. albicans colonization resistance. Although antibiotic treatment enables C. albicans colonization, pharmacologic activation of colonic Hif1a induces CRAMP expression and results in a significant reduction of C. albicans GI colonization and a 50% decrease in mortality from invasive disease. In the setting of antibiotics, Hif1a and Camp (which encodes CRAMP) are required for B. thetaiotamicron–induced protection against C. albicans colonization of the gut. Thus, modulating C. albicans GI colonization by activation of gut mucosal immune effectors may represent a novel therapeutic approach for preventing invasive fungal disease in humans.

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Figure 1: Gastrointestinal colonization levels of Candida spp. in antibiotic-treated adult, germ-free adult mice and in infant to adolescent mice.
Figure 2: Clostridial Firmicutes and Bacteroidetes promote C. albicans GI colonization resistance.
Figure 3: B. theta induces Hif1a and Camp in mouse colons.
Figure 4: L-mimosine–dependent activation of HIf1a and Camp in vivo decreases C. albicans GI colonization and dissemination.

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Acknowledgements

We would like to thank K. Nickerson (University of Nebraska, Lincoln, Nebraska), J. Patton-Vogt (Duquesne University, Pittsburgh, Pennsylvania), R. Wheeler (University of Maine, Orono, Maine) and M. Lorenz (University of Texas Health Science Center, Houston, Texas) for providing the C. albicans strains SN152 (from K. Nickerson), BWP17 (from J.Patton-Vogt), Can098 (from R. Wheeler), WO-1 (from M. Lorenz), 3153A (from M. Lorenz); C. Doern (Children's Medical Center Dallas, Dallas, Texas) for the C. glabrata, C. parapsilosis and C. tropicalis strains; and Y. Iwakura (Institute of Medical Science, Tokyo University, Tokyo, Japan) and J. Kolls (Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania) for the IL-17A–knockout mice. We would like to thank S. Skapek, J. Amatruda, R. DeBerardinis and D. Greenberg for providing helpful comments on the manuscript. This study was supported by the Roberta I. and Norman L. Pollock Fund (A.Y.K.), the Global Probiotics Council Young Investigator Grant for Probiotics (A.Y.K.), US National Institutes of Health (NIH) grant R01 DK060855 (L.V.H.), the Howard Hughes Medical Institute (L.V.H.) and NIH grant P30CA142543 (Y.X.).

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A.Y.K. and L.V.H. conceived and designed the experiments. L.V.H. provided gnotobiotic mice and mucosal immunology instruction and support. A.Y.K., D.F., L.A.C., T.R.S.-W. and M.M.N. performed the experiments. A.Y.K., J.K., M.K., X.Z. and Y.X. conducted microbial profiling and statistical analysis. A.Y.K. and L.V.H. analyzed the data. A.Y.K. wrote the paper.

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Correspondence to Andrew Y Koh.

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Fan, D., Coughlin, L., Neubauer, M. et al. Activation of HIF-1α and LL-37 by commensal bacteria inhibits Candida albicans colonization. Nat Med 21, 808–814 (2015). https://doi.org/10.1038/nm.3871

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