Conflict and Cooperation between AMP Species on the skin

皮肤上AMP物种之间的冲突与合作

• 批准号: 9814329
• 负责人: Richard L Gallo
• 金额: $ 45.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9814329
• 关键词: 3-Dimensional; Animals; Atopic Dermatitis; Attention; Bacteria; Biological Assay; Cells; Clinical Trials; Coagulase; Collection; Complement; Conflict (Psychology); Data; Defensins; Dermis; Disadvantaged; Disease Outcome; Environment; Epidermis; Frequencies; Functional disorder; Genus staphylococcus; Goals; Growth; Host Defense; Human; Immune; Immune system; Inbred BALB C Mice; Inflammation; Inflammatory; Inflammatory Response; Innovative Therapy; Integration Host Factors; Laboratories; Libraries; Measures; Microbe; Mus; Pathogenesis; Patients; Prevalence; Process; Production; Psoriasis; Reactive Oxygen Species; Regulation; Shapes; Skin; Staphylococcus aureus; Swab; Symptoms; System; Testing; Work; antimicrobial; antimicrobial peptide; base; beneficial microorganism; beta-Defensins; cathelicidin; cell type; commensal bacteria; cytokine; defined contribution; improved; in vivo; insight; member; microbiome; mutant; novel therapeutics; pathogen; pathogenic microbe; resident commensals; response; screening; skin disorder; skin microbiome

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.

项目摘要/摘要 人类皮肤免疫系统允许几种菌株存活，这些菌株具有重要的 帮助皮肤免疫防御系统防御病原体和调节 发炎。这项提案的目标是定义可以促进或抑制 人类皮肤微生物群的有益成员。特别是，我们将专注于影响 某些产生抗菌分子的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金黄色葡萄球菌在表皮上竞争生存。我们的前辈 基于实验室的研究、动物研究和临床试验表明，这些细菌 CONS-AM+细菌是皮肤联合免疫防御策略的重要组成部分，其 皮肤上的存在将阻止金黄色葡萄球菌的定植。这在皮肤病中尤为重要。 特应性皮炎(AD)。在AD中，我们观察到cons-AM+缺乏，并被cons株取代 缺乏AM活动(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居住在这种环境中的能力 环境利基。我们的中心假设是，这些分子的产生决定了组成 皮肤微生物组的。为了验证这一假设，我们提出了三个有重点且相互关联的具体目标。在第一个 目的：我们会在皮肤中诱导不同的炎症反应，研究我们所表达的分子 假说将选择cons-AM+比cons-AM-株存活，并检查调节细胞因子 这一过程。在目标2中，我们将注意力集中在微生物本身上，确定宿主因素是如何 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 它还与这个系统相互作用，试图击败CONS-AM+有益细菌。建议数 该项目将使人们更好地了解AD的发病机制，并确定AD皮肤缺乏的机制 可以改善疾病结局的细菌菌株。这些数据将对开发新的和 治疗AD和其他炎症性皮肤病的创新疗法。