STAT3-mediated immunity to Staphylococcus aureus in skin

STAT3介导的皮肤金黄色葡萄球菌免疫

• 批准号: 9055474
• 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: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055474
• 关键词: Abscess; Admission activity; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Autoimmune Process; Candida albicans; Cell physiology; Cells; Chemotaxis; Communities; Complex; Cutaneous; Cytokine Receptors; Cytokine Signaling; Data; Development; Embryo; Epidemic; Focal Infection; Future; Generations; Hospitals; Host Defense; Host Defense Mechanism; Human; Immune; Immune response; Immunity; Immunotherapy; In Vitro; Infection; Infectious Skin Diseases; Inflammation; Interleukin-17; Interleukin-6; Job' s Syndrome; Knockout Mice; Mediating; Multi-Drug Resistance; Mus; Myeloid Cells; Necrosis; Neutrophil Infiltration; Outpatients; Patients; Play; Population; Production; Public Health; Receptor Signaling; Recurrence; Role; Signal Transduction; Skin; Skin Tissue; Skin graft; Soft Tissue Infections; Staphylococcus aureus; Stat3 protein; T cell response; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Translating; Vaccines; Virulent; Visit; Xenograft Model; adaptive immunity; antimicrobial; antimicrobial peptide; base; cytokine; in vivo; in vivo Model; insight; interleukin-22; interleukin-23; keratinocyte; loss of function mutation; methicillin resistant Staphylococcus aureus; mouse model; neutrophil; novel; pathogen; public health relevance; resistant strain; response; trafficking; transcription factor

 DESCRIPTION (provided by applicant): Staphylococcus aureus is responsible for the vast majority of skin infection in humans, which corresponds to 14 million outpatient visits and nearly 500,000 hospital admissions per year in the U.S. Moreover, the epidemic of community-acquired methicillin-resistant S. aureus (CA-MRSA) infections in the past 2 decades has become a serious public health concern, as virulent and multi-drug resistant strains are causing severe and recurrent skin infections in healthy people outside hospital settings. If future immunotherapies and vaccines are to provide an alternative to antibiotics, understanding the cutaneous host defense mechanisms that protect against S. aureus skin infections is essential. In humans, patients with loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) (i.e., hyper-IgE syndrome patients [HIES]) have a deficiency of circulating T helper 17 cells (Th17 cells) and suffer from recurrent S. aureus skin infections. These findings suggest that STAT3 and Th17 cells are important for immune protection against S. aureus skin infections in humans. The role of STAT3 in Th17 responses complex as cytokines that signal via STAT3 (IL-6, IL-23) are thought to promote the generation of Th17 cells (as well as Th22 and IL-17/IL-22-producing γδ T cells) and effector cytokines that signal via STAT3 (IL-6, IL-21 and IL-22) are produced by these cells. Therefore, we used an in vivo mouse model of a CA-MRSA in conjunction with STAT3 cre/lox conditional knockout mice to investigate STAT3-mediated responses among resident skin cells, trafficking of immune cells (including neutrophil recruitment/abscess formation that is crucial for immunity against S. aureus infections) and the development of T cell responses. In our preliminary data, we found that deletion of STAT3 in T cells and especially in keratinocytes resulted in markedly impaired S. aureus bacterial clearance. The host defense role of STAT3 in keratinocytes is a novel finding because it provides an explanation for the contradiction of why S. aureus infections are confined to the skin in HIES patients despite the presence of a systemic deficiency in Th17 cells. Based on these findings, our overall hypothesis is that STAT3 signaling in keratinocytes and T cells interact to promote antimicrobial peptide production, neutrophil recruitment and generation of IL-17/IL-22-producing γδ T cells and Th17/Th22 cells for optimal host defense against S. aureus skin infections. 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, and Aim 3 will evaluate the host defense role of STAT3 in human skin grafts and keratinocytes against S. aureus. The insights gained in this proposal will provide more effective immune mechanisms to target in the future development of immunotherapies and vaccines against S. aureus skin infections in humans.

 描述(申请人提供)：金黄色葡萄球菌是人类皮肤感染的主要原因，相当于美国每年1400万次门诊就诊和近500,000次住院治疗。此外，在过去20年中，社区获得性耐甲氧西林金黄色葡萄球菌(CA-MRSA)感染的流行已经成为一个严重的公共卫生问题，因为毒力和多重耐药菌株正在导致医院以外的健康人发生严重和反复的皮肤感染。如果未来的免疫疗法和疫苗要提供抗生素的替代品，了解防止金黄色葡萄球菌皮肤感染的皮肤宿主防御机制是至关重要的。在人类中，转录因子信号转导和转录激活因子3(STAT3)功能缺失突变的患者(即高IgE综合征患者[HIEs])存在循环辅助性T细胞(Th17细胞)缺陷，并患有反复的金黄色葡萄球菌皮肤感染。这些发现表明，STAT3和Th17细胞对人体皮肤感染金黄色葡萄球菌具有重要的免疫保护作用。STAT3在Th17反应中的作用是作为通过STAT3信号传递信号的细胞因子(IL-6、IL-23)被认为促进Th17细胞(以及产生Th22和IL-17/IL-22的γδT细胞)的产生，并由这些细胞产生通过STAT3信号传递信号的效应性细胞因子(IL-6、IL-21和IL-22)。因此，我们使用CA-MRSA和STAT3 cre/lox条件基因敲除小鼠的体内模型来研究STAT3在常驻皮肤细胞之间的反应、免疫细胞的运输(包括对金黄色葡萄球菌感染的免疫至关重要的中性粒细胞招募/脓肿形成)和T细胞反应的发展。在我们的初步数据中，我们发现T细胞中STAT3的缺失，特别是角质形成细胞中的STAT3的缺失，导致金黄色葡萄球菌的细菌清除明显受损。STAT3在角质形成细胞中的宿主防御作用是一个新的发现，因为它解释了为什么金黄色葡萄球菌感染仅限于HIES患者的皮肤，尽管Th17细胞存在系统性缺陷。基于这些发现，我们的总体假设是，角质形成细胞和T细胞中的STAT3信号相互作用，促进抗菌肽的产生，中性粒细胞的募集，以及产生IL-17/IL-22的γδT细胞和Th17/Th22细胞的产生，从而实现对金黄色葡萄球菌皮肤感染的最佳宿主防御。本研究有三个目的。目标1将评估STAT3在角质形成细胞中的宿主防御作用，目标2将评估STAT3在T细胞亚群中的差异作用，目标3将 评估STAT3在人皮肤移植物和角质形成细胞中对金黄色葡萄球菌的宿主防御作用。从这项提案中获得的见解将为未来针对人类金黄色葡萄球菌皮肤感染的免疫疗法和疫苗的开发提供更有效的免疫机制。