Cutaneous Host Defense Against Bacterial Infections

描述(申请人提供)：这项建议的长期目标是深入了解皮肤宿主防御细菌皮肤病原体的机制。越来越多的研究表明，Toll样受体(Toll-like Receptor，TLRs)可与细菌和其他微生物病原体的成分发生反应，进而启动先天和获得性免疫反应。我们在金黄色葡萄球菌诱导的皮肤溃疡小鼠模型系统中的初步数据表明，TLRs和TLR信号分子在皮肤宿主抵御细菌皮肤感染方面具有重要作用。我们假设，TLRs在启动先天和获得性免疫反应方面发挥了关键作用，这对控制细菌皮肤感染是重要的。我们提出实验来研究TLRs和TLR相关的信号分子在皮肤宿主对最常见的皮肤病原体金黄色葡萄球菌的防御中的作用。将研究TLRs感知感染和产生免疫反应的能力，如产生抗菌肽、招募免疫系统细胞以及启动先天和获得性免疫反应。此外，由于培养的角质形成细胞和人类皮肤标本的表皮角质形成细胞都表达TLRs，我们还将研究人类角质形成细胞在感知和启动皮肤对金黄色葡萄球菌的宿主防御机制中的功能作用。我们相信，从细菌性皮肤感染的TLRs研究中获得的见解将有助于拓宽我们对皮肤宿主防御的理解，并允许迫切需要的新的抗菌疗法，这可能是特别重要的，因为越来越多的细菌菌株对传统抗生素疗法产生抗药性。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to gain insight into mechanisms of cutaneous host defense against bacterial skin pathogens. There are an increasing number of studies demonstrating that Toll-like receptors (TLRs) respond to components of bacteria and other microbial pathogens and subsequently initiate innate and adaptive immune responses. Our preliminary data in a mouse model system of Staphylococcus aureus induced skin ulceration suggest that TLRs and TLR signaling molecules are important in cutaneous host defense against bacterial skin infections. We hypothesize that TLRs play a crucial role in initiating innate and adaptive immune responses that are important in controlling bacterial skin infections. We propose experiments to investigate the role of TLRs and TLR related signaling molecules in cutaneous host defense against the most common skin pathogen, Staphylococcus aureus. The ability of TLRs to sense an infection and to generate immune responses such as production of antimicrobial peptides, recruitment immune system cells, and initiation of innate and adaptive immune responses will be investigated. In addition, since cultured keratinocytes and epidermal keratinocytes from human skin specimens have been shown to express TLRs, we will also investigate the functional role that human keratinocytes have in sensing and initiating cutaneous host defense mechanisms against Staphylococcus aureus in culture. We believe the insights obtained from the study of TLRs in bacterial skin infections will help broaden our understanding of cutaneous host defense and allow for much needed novel antibacterial therapies, which may be of particular importance since there are increasing numbers of bacterial strains that are resistant to conventional antibiotic therapy.