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（由申请人提供）：金黄色葡萄球菌是人类绝大多数皮肤感染的罪魁祸首，在美国，每年有 1,400 万人次门诊就诊，近 50 万人次住院。此外，社区获得性耐甲氧西林金黄色葡萄球菌的流行过去 20 年来，金黄色葡萄球菌 (CA-MRSA) 感染已成为一个严重的公共卫生问题，因为其毒力强且具有多重耐药性。如果未来的免疫疗法和疫苗要提供抗生素的替代品，那么了解金黄色葡萄球菌皮肤感染的皮肤宿主防御机制至关重要。转录因子信号转导子和转录激活子 3 (STAT3) 的功能突变（即高 IgE 综合征患者 [HIES]）缺乏循环 T 辅助细胞 17 (Th17)这些发现表明 STAT3 和 Th17 细胞对于人类抵抗金黄色葡萄球菌皮肤感染的免疫保护很重要。STAT3 作为通过 STAT3 (IL) 发出信号的细胞因子在 Th17 反应复合物中的作用。 -6、IL-23）被认为可促进 Th17 细胞（以及产生 Th22 和 IL-17/IL-22 的 γδ T 细胞）和效应细胞因子的生成，这些细胞因子通过以下途径发出信号： STAT3（IL-6、IL-21 和 IL-22）由这些细胞产生，因此，我们使用 CA-MRSA 体内小鼠模型与 STAT3 cre/lox 条件敲除小鼠一起研究 STAT3 介导的反应。在常驻皮肤细胞中，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募集/脓肿形成）以及 T 细胞反应的发展在我们的初步数据中，我们发现 STAT3 的缺失在T 细胞，尤其是角质形成细胞中的 T 细胞，导致金黄色葡萄球菌细菌清除显着受损。 STAT3 在角质形成细胞中的宿主防御作用是一项新发现，因为它为 HIES 患者中金黄色葡萄球菌感染仅限于皮肤的矛盾提供了解释。尽管 Th17 细胞存在系统性缺陷，但基于这些发现，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和中性粒细胞的募集。产生 IL-17/IL-22 的 γδ T 细胞和 Th17/Th22 细胞，以实现宿主对金黄色葡萄球菌皮肤感染的最佳防御。本研究有三个目标，即评估 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 评估 STAT3 在人类皮肤移植物和角质形成细胞中针对金黄色葡萄球菌的宿主防御作用。本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。