title: Activation of HIF-1α and LL-37 by commensal bacteria inhibits Candida albicans colonization.
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.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Di
authors.initials: D
authors.lastname: Fan
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Coughlin
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Neubauer
authors.affiliation: Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jiwoong
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: 1] Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas. [2] Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Tiffany R
authors.initials: TR
authors.lastname: Simms-Waldrip
authors.affiliation: 1] Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas. [2] Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: 1] Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas. [2] Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas. [3] The Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas. [4] Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Lora V
authors.initials: LV
authors.lastname: Hooper
authors.affiliation: 1] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas. [2] Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. [3] Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Koh
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides; D001439:Bacteroides / Q000187:drug effects / Q000502:physiology*; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development*; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D054804:Cathelicidins / Q000235:genetics / Q000378:metabolism*; D015169:Colony Count, Microbial; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D005856:Germ-Free Life; D019073:HT29 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008898:Mimosine / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008898:Mimosine