Human in vivo Th17 cell responses in cutaneous immunity to Staphylococcus aureus

人体内 Th17 细胞对金黄色葡萄球菌皮肤免疫的反应

• 批准号: 9196957
• 负责人: Lloyd S Miller
• 金额: $ 24.3万
• 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: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196957
• 关键词: AIDS/HIV problem; Abscess; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibodies; Antigens; Area; Biological Models; Blood; CD4 Positive T Lymphocytes; Candida albicans; Cells; Clinical; Clinical Trials; Communities; Cutaneous; DNA Sequence Alteration; Development; Diabetes Mellitus; Epidemic; Failure; Future; Goals; Hematopoietic; Hereditary Disease; Hospitalization; Hospitals; Host Defense; Human; Human Genetics; IgE; Immune; Immune response; Immunity; Individual; Infection; Infectious Skin Diseases; Inpatients; Interleukin-17; Mediating; Multi-Drug Resistance; Mus; Mutation; Myeloid Cells; Neutrophil Infiltration; Outpatients; Patients; Public Health; Recombinants; Recruitment Activity; Research; Role; STAT1 gene; Site; Skin; Staphylococcus aureus; Stem cells; T cell response; T-Lymphocyte; Testing; Translating; Vaccination; Vaccines; Virulent; Visit; White Blood Cell Count procedure; abstracting; adaptive immunity; base; cost; cytokine; humanized mouse; in vivo; in vivo Model; innovation; insight; interest; interleukin-22; methicillin resistant Staphylococcus aureus; mouse model; neutrophil; pre-clinical; prevent; reconstitution; resistant strain; response; stem; vaccination strategy

Project Summary / Abstract The epidemic of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) over the past two decades has resulted in the emergence of virulent and multi-drug resistant strains that are causing severe skin infections in healthy people outside of hospitals. These infections are creating a serious public health concern, especially since antibiotic resistance among CA-MRSA clinical isolates continues to rise. Our ultimate goal is to gain insights into the specific human immune responses that could be targeted for more effective vaccination strategies against S. aureus skin infections. This is especially important because all vaccination attempts against S. aureus to date that were previously effective in preclinical mouse models either had no efficacy in humans or actually exacerbated the infection. The recruitment of neutrophils to the site of infection facilitates abscess formation and is required for clearance of S. aureus skin infections. Thus, in this proposal, we will focus on human Th17 cells and responses since these represent antigen-specific adaptive responses that might control PMN recruitment. However, a major impediment to investigating the mechanisms of human neutrophil recruitment is the lack of an in vivo model system with normal human neutrophil numbers. Current humanized mouse models only possess 1-5% of circulating human neutrophils—far below the 45-70% of neutrophils found in human blood. To overcome this we will develop humanized mice with more efficient neutrophil reconstitution to test our overall hypothesis that the human Th17 cell cytokines IL-17A, IL-22 and IL-26 can promote clearance of a S. aureus skin infection by inducing PMN recruitment. We further hypothesize that S. aureus-specific CD4+ T cells, and in particular Th17 cells, can promote neutrophil recruitment and bacterial clearance. In Aim 1, we will determine the mechanisms by which human IL-17A, IL-22 and IL-26 promote neutrophil recruitment and host defense against a S. aureus skin infection in humanized mice. In Aim 2, we will determine the role of human Th17 cells in promoting PMN recruitment and clearing a S. aureus skin infection in humanized mice. Of note, our humanized mouse models will possess both “matched” human skin and human immune cells, which is highly innovative because this has not been done before to study S. aureus skin infections. Taken together, our proposal will provide new in vivo mechanistic insights by which human Th17 cells and cytokines promote neutrophil recruitment and host defense against S. aureus skin infections. Given that our results will be obtained using optimized humanized in vivo models, our findings are more likely to translate to humans and provide key information about the specific human immune mechanisms to target in the future development of an effective S. aureus vaccine.

项目概要/摘要 过去社区获得性耐甲氧西林金黄色葡萄球菌（CA-MRSA）的流行情况 二十年来导致了剧毒和多重耐药菌株的出现，造成了严重的后果 医院外健康人的皮肤感染这些感染正在造成严重的公共卫生问题。 令人担忧，特别是因为 CA-MRSA 临床分离株的抗生素耐药性持续上升。 目标是深入了解特定的人类免疫反应，这些反应可以针对更有效的目标 针对金黄色葡萄球菌皮肤感染的疫苗接种策略这一点尤其重要，因为所有疫苗接种都是如此。 迄今为止，针对金黄色葡萄球菌的尝试先前在临床前小鼠模型中有效，但没有 中性粒细胞募集到感染部位实际上加剧了感染。 促进脓肿形成，并且是清除金黄色葡萄球菌皮肤感染所必需的。 我们将重点关注人类 Th17 细胞和反应，因为它们代表抗原特异性适应性反应 然而，这可能是研究人类机制的一个主要障碍。 中性粒细胞募集是指缺乏具有正常人类中性粒细胞数量的体内模型系统。 人源化小鼠模型仅拥有 1-5% 的循环人类中性粒细胞，远低于 45-70% 为了克服这个问题，我们将开发出更高效的人源化小鼠。 中性粒细胞重建来检验我们的总体假设，即人类 Th17 细胞细胞因子 IL-17A、IL-22 和 IL-26 可以通过诱导 PMN 募集来促进金黄色葡萄球菌皮肤感染的清除。 研究发现金黄色葡萄球菌特异性 CD4+ T 细胞，特别是 Th17 细胞，可以促进中性粒细胞 在目标 1 中，我们将确定人类 IL-17A、 IL-22 和 IL-26 促进中性粒细胞募集和宿主防御金黄色葡萄球菌皮肤感染 在目标 2 中，我们将确定人类 Th17 细胞在促进 PMN 募集和中的作用。 清除人源化小鼠的金黄色葡萄球菌皮肤感染值得注意的是，我们的人源化小鼠模型将具有 两者都“匹配”人体皮肤和人体免疫细胞，这是高度创新的，因为这还没有被 综上所述，我们的建议将提供新的体内金黄色葡萄球菌皮肤感染研究。 人类 Th17 细胞和细胞因子促进中性粒细胞募集和宿主的机制见解 鉴于我们的结果将使用优化的人源化方法获得。 体内模型，我们的发现更有可能转化为人类并提供有关特定的关键信息 人类免疫机制是未来开发有效金黄色葡萄球菌疫苗的目标。