Innate Immune Response to Staphylococcus aureus in Skin

描述(申请人提供)：由于耐甲氧西林金黄色葡萄球菌(MRSA)和多重耐药菌株的不断出现和发病率的急剧增加，金黄色葡萄球菌皮肤感染已成为美国的一个主要公共卫生威胁。这项应用将侧重于研究中性粒细胞招募和宿主对金黄色葡萄球菌皮肤感染的防御机制，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。根据我们已发表的发现和初步数据，我们假设天然免疫系统对抗金黄色葡萄球菌皮肤感染的主要途径包括Toll样受体(TLRs)识别病原体，分泌IL-1，然后诱导IL-23/IL-17，从而触发中性粒细胞向皮肤募集。我们进一步假设，该途径的不同组成部分可以作为治疗金黄色葡萄球菌皮肤感染的靶点。为了验证这些假设，将使用体内小鼠皮肤金黄色葡萄球菌皮肤感染模型，并结合体内成像技术实时跟踪中性粒细胞招募和细菌清除。此外，创新的人类皮肤培养系统，包括直接来自人类皮肤的特定天然免疫细胞群的培养，器官型角质形成细胞，以及与人中性粒细胞趋化分析相结合的全层人类皮肤移植，将被用于确定在金黄色葡萄球菌感染的背景下促进中性粒细胞招募的主要细胞因子和趋化因子。最后，将开发新的治疗策略，针对人类常驻皮肤固有免疫细胞群，以增加那些被发现在触发中性粒细胞募集中起重要作用的介质的产生。这一应用将对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，这项研究具有很大的翻译潜力，因为开发创新的治疗策略来吸引宿主的中性粒细胞反应将为未来预防和治疗金黄色葡萄球菌皮肤感染提供基础。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抗击这些感染，这些感染对抗生素治疗的耐药性越来越强。 与公共卫生相关。金黄色葡萄球菌皮肤感染在美国是一个主要的公共健康威胁，因为这些感染的发病率急剧增加，以及毒力和抗药性菌株的广泛出现。这项应用的最终目标是揭示宿主对金黄色葡萄球菌皮肤感染的防御机制的新见解，并利用这些见解开发基于免疫的创新治疗策略，为未来预防和治疗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，因为迫切需要新的有效的治疗方式来帮助抗击这些感染，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.