Phagocyte Mutation Interferes with Immune System Control

A mutation causing production of an inactive form of the CX3CR1 (C-X3-C motif chemokine receptor 1) protein in immune system mononuclear phagocytes has been identified as major contributor to the development of Crohn's disease and other types of inflammatory bowel disease (IBD).

Intestinal fungi are an important component of the gut microbiota, and recent studies have unveiled their potential in modulating host immune homeostasis and inflammatory disease. While CX3CR1+ mononuclear phagocytes (MNPs) had been identified as being essential for the initiation of innate and adaptive immune responses to intestinal fungi, and it was known that CX3CR1+ MNPs expressed antifungal receptors and activated antifungal responses, the mechanisms governing immunity to gut fungal communities (mycobiota) remained unknown.

To further understanding in this important area, investigators at Weill Cornell Medicine (New York, NY, USA) used chemical means to induce colitis in mice, and then infected them with fungi to determine whether the fungal cells would overgrow in the mouse gut and increase the severity of the illness.

Results published in the January 12, 2018, issue of the journal Science revealed that mice lacking gut CX3CR1+ phagocytes were more susceptible to intestinal disease than mice that had functional antifungal phagocytes. Antifungal drug treatment significantly reversed symptoms of the disease in mice lacking CX3CR1+ phagocytes, indicating that fungal overgrowth was responsible for the severe response.

The investigators analyzed phagocyte function in a group of more than 500 Crohn’s disease patients. They identified a missense mutation in the gene encoding CX3CR1 and found that it was associated with impaired antifungal responses.

"Our findings show that these CX3CR1+ cells are also essential for the initiation of immune responses to gut fungi, and regulate the composition of the gut mycobiome," said senior author Dr. Iliyan Iliev, assistant professor of microbiology and immunology at Weill Cornell Medicine. "Fungal DNA is hard to access and analyze using standard molecular biology techniques, but we have recently developed much better tools for doing so, and have now taken this further by visualizing fungal-host interactions in the gut. After discovering that fungi might be involved in the pathology of IBD, one of the big questions in the field has been how to identify patients who would benefit from antifungal co-therapy, and our finding suggests a way to do that."

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