Molecular Basis of Host-Microbe Interactions

皮肤是主要的物理屏障，是先天免疫的不可避免的组成部分。皮肤屏障的任何破坏都会使环境的损害和微生物进入人体并建立感染。宿主免疫系统已经发展出维持表皮完整性的机制。其中一个重要的机制就是皮肤的微生物屏障。皮肤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的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，微生物群如何影响免疫系统调节皮肤屏障功能尚不清楚。肥大细胞是在免疫稳态中起重要作用的组织免疫细胞。肥大细胞位于粘膜屏障表面，与微生物群密切接触。共生菌调节肥大细胞的一些表型和功能特征，包括肥大细胞向组织的迁移、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稳态控制的影响尚不清楚。我的研究计划的长期目标是了解互体特异性肥大细胞反应如何促进屏障组织的完整性和稳态。我们已经确定了一种哺乳动物受体系统，它可以拦截细菌的交流，从而对宿主有利。受体Mrgprb2（人类MRGPRX2的同源物）仅在肥大细胞中表达，并识别细菌来源的阳离子分子（带正电）。阳离子分子通过Mrgprb2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了皮肤的再生愈合，表明Mrgprb2/X2在屏障修复中起作用。在接下来的五年里，我的研究计划的短期目标是提供Mrgprb2/X2在宿主-共生相互作用和维持免疫稳态中的具体作用的机制见解。我们提出以下具体目标：1)评估共生菌在Mrgprb2/X2+肥大细胞成熟和功能中的作用；2)研究评论源分子是否能激活Mrgprb2/X2；3)确定Mrgprb2/X2信号的激活是否促进了屏障功能和修复。这项研究具有重要意义，因为它有望揭示皮肤细胞-免疫系统-微生物群串扰在屏障功能和体内平衡中的新的机制见解，这将对我们了解皮肤共生生物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.