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: 7590055
• 负责人: Lloyd S Miller
• 金额: $ 34.65万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590055
• 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）：金黄色葡萄球菌的皮肤感染已成为美国的主要公共卫生威胁，因此，发病率的急剧增加以及持续耐甲氧西林的金黄色葡萄球菌（MRSA）（MRSA）和多耐用耐药菌的持续出现。该应用将着重研究中性粒细胞募集的机制和针对金黄色葡萄球菌感染的宿主防御，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。根据我们发表的发现和初步数据，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（TLRS）的病原体识别IL-1，然后诱导IL-23/IL-17，然后诱导IL-23/IL-17，随后触发了中性幼体的招募。我们进一步假设该途径的不同组成部分可以作为针对金黄色葡萄球菌感染的治疗靶标。为了检验这些假设，将使用体内皮肤链球菌皮肤感染模型以及体内成像技术，以实时跟踪中性粒细胞募集和细菌清除率。 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.最后，将开发出新的治疗策略，以靶向人类居民皮肤先天免疫细胞群体，以增强那些在触发嗜中性粒细胞募集中很重要的介体的产生。该应用将为中性粒细胞募集机制和宿主防御金黄色葡萄球菌皮肤感染提供重要的新见解。此外，这项研究具有巨大的转化潜力，因为开发了吸引宿主的嗜中性粒细胞反应的创新治疗策略将为未来预防和针对金黄色葡萄球菌皮肤感染的治疗干预措施提供基础。我们认为，这种应用是及时且相关的，因为迫切需要对新的有效治疗方式的需求来帮助应对这些感染，这些感染变得越来越对抗生素疗法具有抗药性。 公共卫生相关性。金黄色葡萄球菌皮肤感染代表了美国的主要公共卫生威胁，这是由于这些感染的发病率急剧增加以及耐药和抗生素耐药菌菌株的广泛出现。该应用的最终目标是发现对宿主防御链球菌皮肤感染的机制的新颖见解，并使用这些见解来开发创新的基于免疫的治疗策略，这些策略将为未来的预防和治疗干预措施针对金黄色葡萄球菌皮肤感染提供基础。我们认为，这一研究领域非常重要，因为迫切需要需要新的有效治疗方式来帮助打击这些感染，这些感染变得越来越抗抗生素治疗。