STAT3 and IL-17-Th17 in skin immunity to MRSA

STAT3 和 IL-17-Th17 在皮肤对 MRSA 的免疫中的作用

• 批准号: 8903440
• 负责人: Lloyd S Miller
• 金额: $ 35.64万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-09 至 2015-09-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903440
• 关键词: Acute; Admission activity; Antibiotic Resistance; Bacteria; CD4 Positive T Lymphocytes; CD8B1 gene; Candida; Candida albicans; Cells; Chemotaxis; Chronic; Communities; Cutaneous; Development; Eczema; Embryo; Epidemic; Furuncles; Future; Generations; Hospitals; Host Defense; Host Defense Mechanism; Human; Immune; Immune Targeting; Immune response; Immunity; Impairment; Infection; Infectious Skin Diseases; Inflammatory; Interleukin-17; Job' s Syndrome; Light; Measures; Monitor; Mus; Mutation; Myeloid Cells; Necrosis; Neutrophil Infiltration; Occupations; Outpatients; Pathogenesis; Patients; Phenotype; Play; Production; Psoriasis; Public Health; Rare Diseases; Recurrence; Risk Factors; Role; SCID Mice; Signaling Molecule; Skin; Skin Tissue; Soft Tissue Infections; Staphylococcus aureus; Stat3 protein; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Time; Vaccination; Virulent; Visit; Xenograft Model; antimicrobial; antimicrobial peptide; base; combat; cytokine; extracellular; in vivo; in vivo Model; innovation; keratinocyte; loss of function mutation; methicillin resistant Staphylococcus aureus; mouse model; neutralizing antibody; neutrophil; novel; optical imaging; pathogen; reconstitution; research study; resistant strain; response; skin disorder; transcription factor

Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) in humans, which result in 14 million outpatient visits and half of a million hospital admissions per year in the U.S. Moreover, the epidemic of community-acquired methicillin-resistant S. aureus (CA-MRSA) in the past 2 decades has become an enormous public health threat, as virulent and antibiotic resistant strains are causing severe and necrotic SSTIs in healthy people outside hospital settings (and without risk factors for infection). The experiments in this proposal will build on the observations in humans with the rare orphan disease Hyper-IgE syndrome, who suffer from an eczema-like skin eruption and chronic and recurrent skin infections with S. aureus. These patients were found to have loss-of-function mutations in the signaling molecule STAT3 and a deficiency in Th17 cells, suggesting that STAT3 and IL-17/Th17 responses are essential for cutaneous host defense against S. aureus. Although IL-17/Th17 responses in skin have been implicated in the chronic inflammatory skin disease psoriasis, little is known about the host defense role of IL-17/Th17 responses during an acute MRSA skin infection. The overall hypothesis of this proposal is that STAT3 and IL-17/Th17 protective cutaneous immune responses against MRSA in skin are induced by cytokine cross-talk between keratinocytes and T cells. This study has three aims. Aim 1 will evaluate the host defense role of STAT3 in keratinocytes. Aim 2 will evaluate the differential role of STAT3 in T cell subsets during primary infection and reinfection of MRSA in skin. Aim 3 will determine the mechanisms of STAT3 in human keratinocytes to promote host defense mechanisms, including antimicrobial peptide production and neutrophil responses. To test these hypotheses, we have developed an innovative mouse model S. aureus/MRSA skin infection that combines light-emitting bacteria with in vivo optical imaging to noninvasively monitor the bacterial burden in the infected skin by measuring the amount of emitted light in anesthetized mice over time. In addition, a human skin/SCID mouse xenograft model, human organotypic keratinocyte cultures and keratinocytes from Hyper-IgE syndrome patients. This study will provide a broad and sustained impact to the field by defining the key cutaneous host defense mechanisms against S. aureus/MRSA, an important human bacterial skin pathogen. The proposed experiments will define the cytokine interactions induced by STAT3 between keratinocytes and T cells to promote host defense against MRSA in the skin. Finally, this study may uncover novel cutaneous immune mechanisms that could be targeted in the future development of immune-based therapeutic strategies to help combat S. aureus/MRSA infections in humans.

金黄色葡萄球菌是人类皮肤和软组织感染（SSTI）的最常见原因， 在美国，每年有1400万门诊病人和50万住院病人。 社区获得性耐甲氧西林沙门氏菌的流行金黄色葡萄球菌（CA-MRSA）在过去20年中已成为 这是一个巨大的公共卫生威胁，因为有毒和抗生素耐药菌株正在导致严重和坏死的 SSTI在医院环境外的健康人群中（并且没有感染的风险因素）。这个实验 该提案将建立在对患有罕见孤儿疾病高IgE综合征的人类的观察基础上， 患有湿疹样皮疹和慢性和复发性皮肤感染。金黄色。这些 发现患者在信号分子STAT 3中有功能缺失突变， Th 17细胞，表明STAT 3和IL-17/Th 17应答对于皮肤宿主防御抗 S.金黄色。尽管皮肤中的IL-17/Th 17应答与慢性炎症性皮肤炎有关， 尽管在急性MRSA感染中，IL-17/Th 17应答在银屑病中的宿主防御作用知之甚少， 皮肤感染该建议的总体假设是STAT 3和IL-17/Th 17保护皮肤的免疫应答。 角质形成细胞和T细胞之间细胞因子交互作用诱导皮肤中抗MRSA的免疫应答 细胞本研究有三个目的。目的1研究STAT 3在角质形成细胞中的防御作用。目标2将 评估STAT 3在MRSA初次感染和再感染中T细胞亚群的差异作用， 皮肤目的3探讨STAT 3在人角质形成细胞中促进宿主防御的作用机制 机制，包括抗菌肽的生产和中性粒细胞的反应。为了验证这些假设， 我们开发了一种创新的小鼠模型S。金黄色葡萄球菌/MRSA皮肤感染， 细菌与体内光学成像，以非侵入性地监测感染皮肤中的细菌负荷， 测量麻醉小鼠随时间的发光量。此外，人皮肤/SCID小鼠 异种移植模型、人器官型角质形成细胞培养物和来自高IgE综合征角质形成细胞 患者这项研究将提供一个广泛的和持续的影响，以确定该领域的关键皮肤主机 对S.金黄色葡萄球菌/MRSA，一种重要的人类细菌性皮肤病原体。拟议 实验将确定角质形成细胞和T细胞之间由STAT 3诱导的细胞因子相互作用， 促进宿主防御皮肤中的MRSA。最后，这项研究可能会发现新型皮肤免疫 在未来开发基于免疫的治疗策略时可以靶向的机制， 战斗S。金黄色葡萄球菌/MRSA感染。