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

Nat Med. 2015 Jul;21(7):808-14. doi: 10.1038/nm.3871. Epub 2015 Jun 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Bacteroides / drug effects
  • Bacteroides / physiology*
  • Candida albicans / drug effects
  • Candida albicans / growth & development*
  • Candidiasis / drug therapy
  • Candidiasis / microbiology
  • Candidiasis / pathology
  • Cathelicidins / genetics
  • Cathelicidins / metabolism*
  • Colony Count, Microbial
  • Female
  • Gastrointestinal Tract / drug effects
  • Gastrointestinal Tract / microbiology
  • Gastrointestinal Tract / pathology
  • Germ-Free Life
  • HT29 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice, Inbred C57BL
  • Mimosine / pharmacology

Substances

  • Anti-Bacterial Agents
  • Cathelicidins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • antimicrobial peptide LL-37
  • Mimosine