The 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 might constantly shape host immunity or influence disease. Mucosal immunity to fungi has been largely explored in the context of oral, skin, vaginal or lung infection. Yet very little is known about the role of fungi in influencing immunity in the intestines, where fungal microbiota (mycobiota) is highly abundant and fungal dysbiosis occurs frequently. 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. CD11b+CD103+ DCs and CX3CR1+ MNPs have both the potential to induce Th17 immune responses to 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 affect responses toward intestinal mycobiota. However whether fungal specific Th17 cells arise in the intestines and what 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) interacts with gut mycobiota 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 focus on delineating: (1) role of these phagocytic populations in activation of innate and adaptive responses to fungi in the gut; (2) the mechanisms of gut mycobiota control by gut resident phagocytes; (3) the specific interactions of gut fungi with intestinal phagocytes during intestinal inflammation. Understanding of the immune mechanisms behind host?mycobiota interactions in the gut, would propel the field and facilitate much needed translational studies in inflammatory and infectious diseases where intestinal mycobiota might play a crucial role in disease pathophysiology.
Immunity to fungi has been largely explored in the context of systemic, oral, skin, vaginal or lung infection. Yet very little is known about the role of fungi in influencing immunity in the intestines, where fungi are highly abundant and respond do changes of the host health status. In this proposal, we will study specific cell types, called phagocytes that can interact with fungi in the gut, trigger immunity to these organism to influence our health.
| Leonardi, Irina; Li, Xin; Iliev, Iliyan D (2018) Macrophage interactions with fungi and bacteria in inflammatory bowel disease. Curr Opin Gastroenterol 34:392-397 |
| Li, Xin; Leonardi, Irina; Semon, Alexa et al. (2018) Response to Fungal Dysbiosis by Gut-Resident CX3CR1+ Mononuclear Phagocytes Aggravates Allergic Airway Disease. Cell Host Microbe 24:847-856.e4 |
