Innate Immune Response to Staphylococcus aureus in Skin

描述（由申请人提供）：金黄色葡萄球菌皮肤感染已成为美国主要的公共卫生威胁，其结果是发病率的急剧增加和耐甲氧西林金黄色葡萄球菌的持续出现。金黄色葡萄球菌（MRSA）和多药耐药菌株。本研究将着重于探讨嗜中性粒细胞的募集和宿主对沙门氏菌的防御机制。金黄色葡萄球菌皮肤感染，并使用从了解这些途径获得的信息来开发创新的治疗策略。基于我们已发表的研究结果和初步数据，我们假设先天免疫系统对抗S。金黄色葡萄球菌皮肤感染涉及Toll样受体（TLR）的病原体识别、IL-1的分泌，随后诱导IL-23/IL-17，其随后触发中性粒细胞向皮肤的募集。我们进一步假设该通路的不同组分可以作为抗S.金黄色皮肤感染。为了验证这些假设，在体内小鼠皮肤S。将使用金黄色葡萄球菌皮肤感染模型与体内成像技术的组合来实时跟踪中性粒细胞募集和细菌清除。此外，创新的人皮肤培养系统，包括直接来源于人皮肤、器官型角质形成细胞和全层人皮肤外植体的特异性先天免疫细胞群的培养物，与人中性粒细胞趋化性测定组合，将用于确定在S.金黄色葡萄球菌感染。最后，将开发新的治疗策略，靶向人类固有皮肤先天免疫细胞群，以增强那些介质的产生，这些介质在触发中性粒细胞募集中很重要。这一应用将为研究中性粒细胞募集和宿主防御机制提供重要的新见解。金黄色皮肤感染。此外，这项研究具有重要的转化潜力，因为开发创新的治疗策略来参与宿主的嗜酸性反应将为未来预防和治疗S。金黄色皮肤感染。我们认为，这一应用是及时和相关的，因为迫切需要新的和有效的治疗方式来帮助防治这些感染，这些感染对抗生素治疗的耐药性越来越强。 公共卫生相关性。金黄色葡萄球菌（Staphylococcus aureus）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毒性和抗生素抗性菌株的广泛出现。该应用的最终目的是揭示宿主对S.金黄色葡萄球菌皮肤感染，并利用这些见解开发创新的免疫为基础的治疗策略，将提供基础，为未来的预防和治疗干预措施，对金黄色葡萄球菌。金黄色皮肤感染。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感染，这些感染对抗生素治疗的耐药性越来越强。

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.