Mononuclear phagocyte networks in mycobiota regulation and antifungal immunity.

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Abstract Intestinal fungi are an important component of the microbiota, and recent studies have unveiled their potential in modulating inflammatory disease. Mucosal immunity to fungi has been largely explored in the context of oral, skin, vaginal or lung infection. Nonetheless, the mechanisms governing immunity to gut fungi (mycobiota) remain unknown. We have shown that a polymorphism in the human gene encoding the anti-fungal receptor Dectin-1 (CLEC7A) is strongly associated with severity of ulcerative colitis and that, in a mouse models of colitis and lung allergy, fungal dysbiosis can contribute to intestinal and lung inflammation. This suggests that intestinal immunity to fungi may be an important factor in shaping host immunity. As a central hub of mucosal immunity, the gastrointestinal tract is naturally equipped with a cellular machinery to recognize and interact with the microbiota populating this body site. The intestines harbor several subsets of phagocytes, which are known to respond to bacterial infections or to fluctuations in commensal bacterial communities. These intestinal phagocyte subsets comprise of conventional dendritic cells (DCs), most of which express the integrin CD103 albeit different levels of CD11b, and intestinal MNPs which express high levels of CX3CR1. CX3CR1+ MNPs and CD103+ DCs have the potential to induce antigen specific T helper responses to commensal and pathogenic bacteria in the gut. We and others have shown that Dectin-1/ CARD9 axis is crucial for the induction of antifungal Th17 immunity at several barrier sites and can affect responses toward intestinal mycobiota. However how intestinal phagocyte networks coordinate gut fungal sensing and immunity to mycobiota is currently unknown. It is becoming increasingly clear that an aberrant pro-inflammatory response to microbiota by infiltrating monocytes plays a role in the development of intestinal inflammation. Our data show that intestinal mononuclear phagocytes with characteristics of macrophages play an important role in limiting fungal overgrowth in the gut, and can be influenced by the inflammatory environment to further propel inflammation. We further show that a specific subset of CX3CR1+ gut mononuclear phagocytes (MNPs) interacts with bona- fide gut fungi to trigger innate and adaptive immune responses to fungi. Employing conditional knock out in vivo models, model fungal strains, high-throughput platforms for fungal and bacterial sequencing, targeting of fungi with drugs, and computational pipelines, we will define how phagocytes control immunity to fungi in the gut to influence states of health and inflammatory disease. Better understanding of the interaction of intestinal phagocytes with commensal fungi, would provide an opportunity for the development of more targeted therapies for inflammatory diseases.