Innate Immune Regulation of Mycobiota During Health and Disease.

AbstractThe majority of studies on the impact of microbiota on immunity have focused on bacteria and viruses. However,the mammalian barrier surfaces are also a natural environment where commensal fungi reside and mightconstantly shape host immunity or influence disease. Mucosal immunity to fungi has been largely explored inthe context of oral, skin, vaginal or lung infection. Yet very little is known about the role of fungi in influencingimmunity in the intestines, where fungal microbiota (mycobiota) is highly abundant and fungal dysbiosis occursfrequently. 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 lungallergy, fungal dysbiosis can contribute to intestinal and lung inflammation. This suggests that intestinal immunityto 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 machineryto recognize and interact with the microbiota populating this body site. The intestines harbor several subsets ofphagocytes, which are known to respond to bacterial infections or to fluctuations in commensal bacterialcommunities. These intestinal phagocyte subsets comprise of conventional dendritic cells (DCs), most of whichexpress the integrin CD103 albeit different levels of CD11b, and intestinal MNPs which express high levels ofCX3CR1. CD11b+CD103+ DCs and CX3CR1+ MNPs have both the potential to induce Th17 immune responsesto commensal and pathogenic bacteria in the gut. Th17 cells are not only important to control bacterial infections,but also play a central role in control of fungi at several barrier surfaces. We and others have shown that Dectin-1/ CARD9 axis (which is crucial for the induction of antifungal Th17 immunity at several barrier sites) can affectresponses toward intestinal mycobiota. However whether fungal specific Th17 cells arise in the intestines andwhat are the phagocytic populations involved in sensing fungi to induce such responses is currently unknown.Our preliminary data show that a specific subset of CX3CR1+ gut mononuclear phagocytes (MNPs) interactswith gut mycobiota to trigger innate and adaptive immune responses to fungi. Employing conditional knock outin vivo models, model fungal strains, high-throughput platforms for fungal and bacterial sequencing, targeting offungi with drugs, and computational pipelines, we will focus on delineating: (1) role of these phagocyticpopulations in activation of innate and adaptive responses to fungi in the gut; (2) the mechanisms of gutmycobiota control by gut resident phagocytes; (3) the specific interactions of gut fungi with intestinal phagocytesduring intestinal inflammation. Understanding of the immune mechanisms behind host?mycobiota interactionsin the gut, would propel the field and facilitate much needed translational studies in inflammatory and infectiousdiseases where intestinal mycobiota might play a crucial role in disease pathophysiology.