Conflict and Cooperation between AMP Species on the skin

项目总结/摘要 人体皮肤免疫系统允许几种细菌株的生存，这些细菌株在人体内发挥重要作用。 功能，以协助皮肤免疫防御系统防御病原体和调节 炎症本提案的目标是确定能够促进或抑制 人类皮肤微生物组的有益成员。特别是，我们将重点关注影响 某些产生抗菌分子凝固酶阴性葡萄球菌（CoNS）菌株的存活 (AMs)（CoNS-AM+）。这些有益的微生物与S.金黄色葡萄球菌在表皮上的生存。我们事先 基于实验室的研究、动物研究和这些细菌的临床试验的工作表明， CoNS-AM+细菌是皮肤的联合免疫防御策略的重要组成部分，其 存在于皮肤上将阻止S.金黄色。这在皮肤病中尤为重要 特应性皮炎（AD）。在AD中，我们已经观察到CoNS-AM+是缺陷的，并且被CoNS菌株取代。 缺乏AM活性的细胞（CoNS-AM-）。令人信服的初步证据现在已经确定了特定的分子 由表皮和核心微生物群产生，这些微生物群塑造了其他微生物栖息于此的能力。 环境生态位我们的中心假设是这些分子的产生决定了 皮肤微生物组的变化。为了验证这一假设，我们提出了3个重点和相互关联的具体目标。上 我们的目的是在皮肤中诱导不同的炎症反应，研究我们所关注的分子的表达， 假设将选择CoNS-AM+而不是CoNS-AM-菌株的存活，并检查调节 这个过程在目标2中，我们将注意力集中在微生物本身，确定宿主因素如何影响 与微生物相互作用。最后，在目标3中，我们介绍了有害微生物的重要变量以及如何 它还与该系统相互作用以试图胜过CoNS-AM+有益细菌。拟议 该项目将带来更好地了解AD的发病机制，并确定AD皮肤缺乏的机制。 可以改善疾病结果的细菌菌株。这些数据对于开发新的和 用于AD和其他炎症性皮肤病的创新疗法。

Project Summary/Abstract The human skin immune system permits survival of several strains of bacteria that perform important functions to assist the skin immune defense system in defense against pathogens and regulation of inflammation. The goal of this proposal is to define factors that can promote or inhibit the survival of the beneficial members of the human skin microbiome. In particular, we will focus on molecules that influence survival of some strains of coagulase-negative staphylococci (CoNS) that produce antimicrobial molecules (AMs) (CoNS-AM+). These beneficial microbes compete with S. aureus for survival on the epidermis. Our prior work from laboratory based studies, animal studies and clinical trials with these bacteria have shown that CoNS-AM+ bacteria are an important part of the combined immune defense strategy of the skin, and their presence on skin will preclude colonization by S. aureus. This is particularly important in the skin disease atopic dermatitis (AD). In AD we have observed that CoNS-AM+ are deficient and replaced by strains of CoNS that lack AM activity (CoNS-AM-). Compelling preliminary evidence has now identified specific molecules produced by the epidermis and the core microbiome that shape the capacity of other microbes to inhabit this environmental niche. Our central hypothesis is that the production of these molecules dictates the composition of the skin microbiome. To test this hypothesis we propose 3 focused and inter-related specific aims. In the first aim will we induce divergent inflammatory responses in the skin, study the expression of the molecules that we hypothesize will select for survival of CoNS-AM+ over CoNS-AM- strains, and examine cytokines that regulate this process. In Aim 2 we focus attention on the microbes themselves, determining how the host factors interact with the microbe. Finally, in Aim 3 we introduce the important variable of the harmful microbe and how it also interacts with this system to attempt to outcompete CoNS-AM+ beneficial bacterial. The proposed project will bring better understanding of the pathogenesis of AD, and define mechanisms why AD skin lacks bacterial strains that can improve disease outcome. These data will be important in developing new and innovative therapies for AD and other inflammatory skin disorders.