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

Di Fan, Laura A. Coughlin, Megan M. Neubauer, Jiwoong Kim, Min Soo Kim, Xiaowei Zhan, Tiffany R Simms-Waldrip, Yang Xie, Lora V Hooper, Andrew Koh

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

Candida albicans colonization is required for invasive disease. Unlike humans, adult mice with mature intact gut microbiota are resistant to C. albicans gastrointestinal (GI) colonization, 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.

Original languageEnglish (US)
Pages (from-to)808-814
Number of pages7
JournalNature Medicine
Volume21
Issue number7
DOIs
StatePublished - Jun 8 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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