Molecular Basis of Host-Microbe Interactions

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Skin is the primary physical barrier and an inevitable constituent of innate immunity. Any compromise of the skin barrier allows environmental insults and microorganisms to enter into the body and establish infection. The host immune system has developed mechanisms to maintain epidermal integrity. One such prominent mechanism is the microbiome barrier of the skin. Skin-resident microbes actively engage functional immune networks of the skin. The outcome of this threefold conversation among cells, the immune system, and the microbiome of the skin is a critical determinant of barrier function and cutaneous homeostasis. However, how the microbiome influences the immune system in modulating skin barrier function is not well understood. Mast cells are tissue-resident immune cells with critical function in immunological homeostasis. Being at the mucosal barrier surfaces, mast cells are in close contact with the microbiota. Commensal bacteria modulate several phenotypic and functional characteristics of mast cells, including their migration to tissue, maturation, function and survival. The role of microbiome-mast cell interaction and its effect on the homeostatic control of the skin barrier function remains undefined. The long-term goal of my research program is to understand how commensal-specific mast cell responses contribute to barrier tissue integrity and homeostasis. We have identified a mammalian receptor system that intercepts bacterial communication to the host's advantage. The receptor Mrgprb2 (ortholog of human MRGPRX2) expresses exclusively in mast cells and recognizes bacteria-derived molecules that are cationic (positively charged). Activation of mast cells via Mrgprb2 by cationic molecules clears bacteria from the skin and the respiratory and gastrointestinal tracts of mice and controls reinfection. Moreover, treatment with cationic molecules augments regenerative healing of the skin, suggesting a role for Mrgprb2/X2 in barrier repair. Over the next five years, the short-term goal of my research program is to provide mechanistic insights into the specific role of Mrgprb2/X2 in host-commensal interactions and the maintenance of immune homeostasis. We propose the following Specific Aims: 1) Evaluate the role of commensal bacteria in the maturation and function of Mrgprb2/X2+ mast cells; 2) Investigate if commensal-derived molecules can activate Mrgprb2/X2; and 3) Determine whether activation of Mrgprb2/X2 signaling promotes barrier function and repair. The proposed research is significant because it is expected to reveal novel mechanistic insights into skin cells-immune system-microbiome crosstalk in barrier function and homeostasis, which will make important contributions to our knowledge of how the skin commensals educate and fine-tune the cutaneous immune system.