Molecular Basis of Host-Microbe Interactions

皮肤是主要的物理屏障，也是先天免疫的必然组成部分。皮肤屏障的任何损害都允许环境损害和微生物进入体内并建立感染。宿主免疫系统已经发展出维持表皮完整性的机制。其中一个突出的机制是皮肤的微生物屏障。皮肤驻留微生物积极参与皮肤的功能性免疫网络。细胞、免疫系统和皮肤微生物组之间这三重对话的结果是屏障功能和皮肤稳态的关键决定因素。然而，微生物组如何影响免疫系统调节皮肤屏障功能尚不清楚。肥大细胞是组织驻留的免疫细胞，在免疫稳态中具有关键功能。在粘膜屏障表面，肥大细胞与微生物群密切接触。共生细菌调节肥大细胞的几种表型和功能特征，包括它们向组织的迁移、成熟、功能和存活。微生物组-肥大细胞相互作用的作用及其对皮肤屏障功能的稳态控制的影响仍然不确定。我的研究计划的长期目标是了解肥大细胞特异性反应如何促进屏障组织的完整性和稳态。我们已经确定了一个哺乳动物受体系统，拦截细菌通信的主机的优势。受体Mrgprb 2（人MRGPRX 2的直系同源物）仅在肥大细胞中表达，并识别细菌衍生的阳离子分子（带正电荷）。阳离子分子通过Mrgprb 2激活肥大细胞，清除小鼠皮肤、呼吸道和胃肠道中的细菌，并控制再感染。此外，用阳离子分子治疗增强皮肤的再生愈合，表明Mrgprb 2/X2在屏障修复中的作用。在接下来的五年里，我的研究计划的短期目标是提供Mrgprb 2/X2在宿主-宿主相互作用和维持免疫稳态中的特定作用的机制见解。我们提出了以下具体目的：1）评价肠道细菌在Mrgprb 2/X2+肥大细胞成熟和功能中的作用; 2）研究肠道衍生分子是否可以激活Mrgprb 2/X2; 3）确定Mrgprb 2/X2信号传导的激活是否促进屏障功能和修复。这项研究意义重大，因为它有望揭示皮肤细胞-免疫系统-微生物组在屏障功能和稳态中相互作用的新机制，这将为我们了解皮肤细胞如何教育和微调皮肤免疫系统做出重要贡献。

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.