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， 导致1400万个门诊就诊，每年在美国接受住院的一半，此外， 在过去的20年中 巨大的公共卫生威胁，因为有毒和抗生素抗性菌株正在引起严重和坏死 医院环境外健康人员的SSTI（没有感染的危险因素）。其中的实验 提案将建立在人类的观察结果的基础上 患有湿疹样的皮肤喷发，以及金黄色葡萄球菌的慢性和复发性皮肤感染。这些 发现患者在信号分子STAT3中具有功能丧失突变，并且缺乏 Th17细胞，表明STAT3和IL-17/TH17反应对于皮肤宿主防御至关重要 S.金黄色葡萄酒。尽管皮肤中的IL-17/TH17反应已与慢性炎症性皮肤有关 疾病牛皮癣，对急性MRSA期间IL-17/TH17反应的宿主防御作用知之甚少 皮肤感染。该提议的总体假设是STAT3和IL-17/TH17保护性皮肤 角质形成细胞和T之间的细胞因子串扰诱导了针对皮肤中MRSA的免疫反应 细胞。这项研究有三个目标。 AIM 1将评估STAT3在角质形成细胞中的宿主防御作用。 AIM 2意志 评估STAT3在原发性感染过程中STAT3在T细胞亚群中的差异作用，并在MRSA中重新感染 皮肤。 AIM 3将确定人角质形成细胞中Stat3的机制促进宿主防御 机制，包括抗菌肽的产生和中性粒细胞反应。为了检验这些假设， 我们已经开发了一种创新的小鼠模型S.金黄色素器/MRSA皮肤感染，结合了发光 带有体内光学成像的细菌，可无创地监测受感染皮肤的细菌负担 随着时间的推移，测量麻醉小鼠中发出的光量。另外，人类的皮肤/SCID鼠标 异种移植模型，Hyper-Ige综合征的人体器官角质形成细胞培养物和角质形成细胞 患者。这项研究将通过定义关键皮肤宿主对现场产生广泛而持续的影响 针对金黄色葡萄球菌/MRSA的防御机制，这是一种重要的人类细菌皮肤病原体。提议 实验将定义角质形成细胞和T细胞之间STAT3引起的细胞因子相互作用 促进对皮肤中MRSA的宿主防御。最后，这项研究可能会发现新颖的皮肤免疫 可能针对未来基于免疫的治疗策略的机制来帮助 战斗S.金黄色葡萄球菌/MRSA感染。