Intestinal colonization by Candida albicans alters inflammatory responses in Bruton's tyrosine kinase-deficient mice.
The commensal yeast Candida albicans is part of the human intestinal microflora and is considered a "pathobiont", a resident microbe with pathogenic potential yet harmless under normal conditions. The aim of this study was to investigate the effect of C. albicans on inflammation of the intestinal tract and the role of Bruton's tyrosine kinase (Btk). Btk is an enzyme that modulates downstream signaling of multiple receptors involved in innate and adaptive immunity, including the major anti-fungal receptor Dectin-1. Colitis was induced in wild type and Btk-/- mice by treatment with dextran sodium sulfate (DSS) and the gastrointestinal tract of selected treatment groups were then colonized with C. albicans. Colonization by C. albicans neither dampened nor exacerbated inflammation in wild type mice, but colon length and spleen weight were improved in Btk-deficient mice colonized with C. albicans. Neutrophil infiltration was comparable between wild type and Btk-/- mice, but the knockout mice displayed severely reduced numbers of macrophages in the colon during both DSS and DSS/Candida treatment. Smaller numbers and reduced responsiveness of Btk-/- macrophages might partially explain the improved colon length of Btk-/- mice as a result of Candida colonization. Surprisingly, DSS/Candida-treated Btk-/- animals had higher levels of certain pro-inflammatory cytokines and levels of the anti-inflammatory cytokine TGF-β were reduced compared to wild type. A clustering and correlation analysis showed that for wild type animals, spleen TGF-β and colon IL-10 and for Btk-/- spleen and colon levels of IL-17A best correlated with the inflammatory parameters. We conclude that in Btk-/- immunocompromised animals, colonization of the gastrointestinal tract by the commensal yeast C. albicans alters inflammatory symptoms associated with colitis.
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
Karin
K
Strijbis
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
Omer H
OH
Yilmaz
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
Stephanie K
SK
Dougan
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
Alexandre
A
Esteban
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Andrea
A
Gröne
Department of Molecular Biology and Microbiology, School of Medicine, Tufts University, Boston, Massachusetts, United States of America.
Carol A
CA
Kumamoto
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
Hidde L
HL
Ploegh
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002176:Candida albicans / Q000276:immunology* / Q000502:physiology; D002177:Candidiasis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D016264:Dextran Sulfate / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D018345:Mice, Knockout; D009929:Organ Size / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D018836:Inflammation Mediators; D020381:Interleukin-17; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D016264:Dextran Sulfate; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse