Innate Immune Response to Staphylococcus aureus in Skin

对皮肤金黄色葡萄球菌的先天免疫反应

• 批准号: 8213386
• 负责人: Lloyd S Miller
• 金额: $ 33.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2012-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213386
• 关键词: Abscess; Antibiotic Resistance; Antibiotic Therapy; Area; Biological Assay; Blocking Antibodies; Cell Adhesion Molecules; Cells; Chemotaxis; Cutaneous; Data; Defect; Dendritic Cells; Development; Family member; Future; Generations; Granulopoiesis; Host Defense; Host Defense Mechanism; Human; Imaging Techniques; Imaging technology; Immune; Immune response; Immune system; In Vitro; Incidence; Infection; Infectious Skin Diseases; Interleukin-1; Interleukin-12; Interleukin-17; Intervention; Langerhans cell; Mediating; Mediator of activation protein; Modality; Modeling; Multi-Drug Resistance; Mus; Neutrophil Infiltration; Pathway interactions; Population; Predisposition; Prevention; Production; Public Health; Publishing; Receptor Activation; Research; Role; Signal Transduction; Site; Skin; Staphylococcus aureus; Syringes; System; T-Lymphocyte; TLR2 gene; Testing; Therapeutic; Thick; Time; Toll-like receptors; Translating; Virulent; base; chemokine; combat; cytokine; effective therapy; human disease; in vivo; in vivo Model; innovation; insight; interleukin-23; keratinocyte; macrophage; mast cell; methicillin resistant Staphylococcus aureus; mouse model; neutrophil; novel; novel therapeutics; pathogen; public health relevance; research study; resistant strain; response; therapeutic target; yellow-1

DESCRIPTION (provided by applicant): Staphylococcus aureus skin infections have emerged as a major public health threat in the U.S. as a result the dramatic increase in incidence and the ongoing emergence of methicillin-resistant S. aureus (MRSA) and multi-drug resistant strains. This application will focus on investigating mechanisms of neutrophil recruitment and host defense against S. aureus skin infections and using the information gained from understanding these pathways to develop innovative therapeutic strategies. Based on our published findings and preliminary data, we hypothesize that a major pathway by which the innate immune system combats S. aureus skin infections involves pathogen recognition by Toll-like receptors (TLRs), secretion of IL-1 followed by induction of IL-23/IL-17, which subsequently triggers neutrophil recruitment to the skin. We further hypothesize that different components of this pathway can serve as therapeutic targets against S. aureus skin infections. To test these hypotheses, an in vivo mouse cutaneous S. aureus skin infection model in combination with in vivo imaging techniques to track both the neutrophil recruitment and bacterial clearance in real-time will be used. In addition, innovative human skin culture systems, including cultures of specific innate immune cell populations derived directly from human skin, organotypic keratinocytes, and full thickness human skin explants in combination with human neutrophil chemotaxis assays will be used to determine the predominant cytokines and chemokines that promote neutrophil recruitment in the context of S. aureus infection. Lastly, novel therapeutic strategies will be developed that target human resident skin innate immune cell populations to enhance production of those mediators found to be important in triggering neutrophil recruitment. This application will provide important new insights into mechanisms of neutrophil recruitment and host defense S. aureus skin infections. Furthermore, this study has significant translational potential, since the development of innovative therapeutic strategies to engage the host's neutrophilic response will provide the groundwork for future prevention and treatment interventions against S. aureus skin infection. We believe that this application is timely and relevant, since the need for new and effective treatment modalities are desperately needed to help combat these infections, which are becoming increasingly resistant to antibiotic therapy. PUBLIC HEALTH RELEVANCE. Staphylococcus aureus skin infections represent a major public health threat in the U.S. as a result of the dramatic increased incidence of these infections and the widespread emergence of virulent and antibiotic- resistant strains. The ultimate objective of this application is to uncover novel insights into mechanisms of host defense against S. aureus skin infection and to use these insights to develop innovative immune-based therapeutic strategies that will provide the groundwork for future prevention and treatment interventions against S. aureus skin infections. We believe that this area of research is highly significant, since the need for new and effective treatment modalities are desperately needed to help combat these infections, which are becoming increasingly resistant to antibiotic therapy.

描述（由申请人提供）：由于发病率急剧上升以及耐甲氧西林金黄色葡萄球菌 (MRSA) 和多重耐药菌株的持续出现，金黄色葡萄球菌皮肤感染已成为美国的主要公共卫生威胁。该应用将重点研究中性粒细胞招募和宿主防御金黄色葡萄球菌皮肤感染的机制，并利用从了解这些途径中获得的信息来开发创新的治疗策略。根据我们发表的研究结果和初步数据，我们假设先天免疫系统对抗金黄色葡萄球菌皮肤感染的主要途径涉及 Toll 样受体 (TLR) 识别病原体、分泌 IL-1，然后诱导 IL-1。 23/IL-17，随后触发中性粒细胞募集到皮肤。我们进一步假设该途径的不同成分可以作为金黄色葡萄球菌皮肤感染的治疗靶点。为了测试这些假设，将使用体内小鼠皮肤金黄色葡萄球菌皮肤感染模型与体内成像技术相结合，以实时跟踪中性粒细胞募集和细菌清除。此外，创新的人类皮肤培养系统，包括直接源自人类皮肤的特定先天免疫细胞群、器官型角质形成细胞和全层人类皮肤外植体的培养物，与人类中性粒细胞趋化性测定相结合，将用于确定主要的细胞因子和趋化因子在金黄色葡萄球菌感染的情况下促进中性粒细胞募集。最后，将开发针对人类常驻皮肤先天免疫细胞群的新治疗策略，以增强那些对触发中性粒细胞募集很重要的介质的产生。该应用将为中性粒细胞募集和宿主防御金黄色葡萄球菌皮肤感染的机制提供重要的新见解。此外，这项研究具有显着的转化潜力，因为开发创新的治疗策略来参与宿主的中性粒细胞反应将为未来针对金黄色葡萄球菌皮肤感染的预防和治疗干预措施奠定基础。我们相信这一应用是及时且相关的，因为迫切需要新的有效的治疗方式来帮助对抗这些对抗生素治疗越来越耐药的感染。 公共卫生相关性。金黄色葡萄球菌皮肤感染是美国的一个主要公共卫生威胁，因为这些感染的发病率急剧增加，并且剧毒和抗生素耐药菌株广泛出现。该应用的最终目标是揭示宿主防御金黄色葡萄球菌皮肤感染机制的新见解，并利用这些见解开发基于免疫的创新治疗策略，为未来针对金黄色葡萄球菌的预防和治疗干预奠定基础皮肤感染。我们认为，这一研究领域非常重要，因为迫切需要新的有效治疗方式来帮助对抗这些对抗生素治疗越来越耐药的感染。