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

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          Abstract

          Candida albicans colonization is required for invasive disease 1- 3 . Unlike humans, adult mice with mature intact gut microbiota are resistant to C. albicans gastrointestinal (GI) colonization 2, 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 HIF-1α, a transcription factor important for activating innate immune effectors, and the antimicrobial peptide LL37-CRAMP are key determinants of C. albicans colonization resistance. While 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 Cramp are required for B. thetaiotamicron-induced protection against CA colonization of the gut. Thus, C. albicans GI colonization modulation by activation of gut mucosal immune effectors may represent a novel therapeutic approach for preventing invasive fungal disease in humans.

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          Most cited references 34

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          An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.

          The mammalian gastrointestinal tract harbors a complex ecosystem consisting of countless bacteria in homeostasis with the host immune system. Shaped by evolution, this partnership has potential for symbiotic benefit. However, the identities of bacterial molecules mediating symbiosis remain undefined. Here we show that, during colonization of animals with the ubiquitous gut microorganism Bacteroides fragilis, a bacterial polysaccharide (PSA) directs the cellular and physical maturation of the developing immune system. Comparison with germ-free animals reveals that the immunomodulatory activities of PSA during B. fragilis colonization include correcting systemic T cell deficiencies and T(H)1/T(H)2 imbalances and directing lymphoid organogenesis. A PSA mutant of B. fragilis does not restore these immunologic functions. PSA presented by intestinal dendritic cells activates CD4+ T cells and elicits appropriate cytokine production. These findings provide a molecular basis for host-bacterial symbiosis and reveal the archetypal molecule of commensal bacteria that mediates development of the host immune system.
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            Symbiotic bacteria direct expression of an intestinal bactericidal lectin.

            The mammalian intestine harbors complex societies of beneficial bacteria that are maintained in the lumen with minimal penetration of mucosal surfaces. Microbial colonization of germ-free mice triggers epithelial expression of RegIIIgamma, a secreted C-type lectin. RegIIIgamma binds intestinal bacteria but lacks the complement recruitment domains present in other microbe-binding mammalian C-type lectins. We show that RegIIIgamma and its human counterpart, HIP/PAP, are directly antimicrobial proteins that bind their bacterial targets via interactions with peptidoglycan carbohydrate. We propose that these proteins represent an evolutionarily primitive form of lectin-mediated innate immunity, and that they reveal intestinal strategies for maintaining symbiotic host-microbial relationships.
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              Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis.

              The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease. Here, we show that the mammalian gut contains a rich fungal community that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility to chemically induced colitis, which was the result of altered responses to indigenous fungi. In humans, we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together, our findings reveal a eukaryotic fungal community in the gut (the "mycobiome") that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                5 May 2015
                08 June 2015
                July 2015
                01 January 2016
                : 21
                : 7
                : 808-814
                Affiliations
                [1 ]Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
                [2 ]Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas
                [3 ]Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas
                [4 ]Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
                [5 ]Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas
                [6 ]The Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX
                [7 ]Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas
                Author notes
                Corresponding author: Andrew Y. Koh, M.D., University of Texas Southwestern Medical Center, Departments of Pediatrics and Microbiology, 5323 Harry Hines Boulevard, Dallas, TX 75390-9063. Phone: 214 648-8802; Fax: 214 648-3122; andrew.koh@ 123456utsouthwestern.edu
                Article
                NIHMS686748
                10.1038/nm.3871
                4496259
                26053625
                Categories
                Article

                Medicine

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