RESUMO
Intestinal fungi are an important component of the microbiota, and recent studies have unveiled their potential in modulating host immune homeostasis and inflammatory disease. Nonetheless, the mechanisms governing immunity to gut fungal communities (mycobiota) remain unknown. We identified CX3CR1+ mononuclear phagocytes (MNPs) as being essential for the initiation of innate and adaptive immune responses to intestinal fungi. CX3CR1+ MNPs express antifungal receptors and activate antifungal responses in a Syk-dependent manner. Genetic ablation of CX3CR1+ MNPs in mice led to changes in gut fungal communities and to severe colitis that was rescued by antifungal treatment. In Crohn's disease patients, a missense mutation in the gene encoding CX3CR1 was identified and found to be associated with impaired antifungal responses. These results unravel a role of CX3CR1+ MNPs in mediating interactions between intestinal mycobiota and host immunity at steady state and during inflammatory disease.
Assuntos
Receptor 1 de Quimiocina CX3C/análise , Receptor 1 de Quimiocina CX3C/genética , Candida albicans/imunologia , Microbioma Gastrointestinal/imunologia , Intestinos/microbiologia , Micobioma/imunologia , Fagócitos/imunologia , Animais , Anticorpos Antifúngicos/biossíntese , Anticorpos Antifúngicos/sangue , Candida albicans/crescimento & desenvolvimento , Colite/tratamento farmacológico , Colite/microbiologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Células Dendríticas/imunologia , Microbioma Gastrointestinal/fisiologia , Humanos , Imunidade nas Mucosas , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Intestinos/imunologia , Camundongos , Mutação de Sentido Incorreto , Micobioma/fisiologia , Fagócitos/microbiologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologiaRESUMO
Compared to bacteria, the role of fungi within the intestinal microbiota is poorly understood. In this study we investigated whether the presence of a "healthy" fungal community in the gut is important for modulating immune function. Prolonged oral treatment of mice with antifungal drugs resulted in increased disease severity in acute and chronic models of colitis, and also exacerbated the development of allergic airway disease. Microbiota profiling revealed restructuring of fungal and bacterial communities. Specifically, representation of Candida spp. was reduced, while Aspergillus, Wallemia, and Epicoccum spp. were increased. Oral supplementation with a mixture of three fungi found to expand during antifungal treatment (Aspergillus amstelodami, Epicoccum nigrum, and Wallemia sebi) was sufficient to recapitulate the exacerbating effects of antifungal drugs on allergic airway disease. Taken together, these results indicate that disruption of commensal fungal populations can influence local and peripheral immune responses and enhance relevant disease states.
