Cutaneous Host Defense Against Bacterial Infections

描述（由申请人提供）：本提案的长期目标是深入了解皮肤宿主防御细菌性皮肤病原体的机制。越来越多的研究表明toll样受体（TLRs）对细菌和其他微生物病原体的成分作出反应，并随后启动先天和适应性免疫反应。我们在金黄色葡萄球菌诱导皮肤溃疡的小鼠模型系统中的初步数据表明，TLR和TLR信号分子在皮肤宿主防御细菌性皮肤感染中起重要作用。我们假设tlr在启动先天性和适应性免疫反应中起着至关重要的作用，这在控制细菌性皮肤感染中很重要。我们拟通过实验研究TLR及其相关信号分子在皮肤宿主防御最常见的皮肤病原体金黄色葡萄球菌中的作用。tlr感知感染和产生免疫反应的能力，如抗菌肽的产生、免疫系统细胞的募集以及先天和适应性免疫反应的启动，将被研究。此外，由于人类皮肤标本中培养的角质形成细胞和表皮角质形成细胞已被证明表达tlr，我们还将研究人类角质形成细胞在感知和启动皮肤宿主防御金黄色葡萄球菌方面的功能作用。我们相信从细菌性皮肤感染的tlr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，并允许急需的新型抗菌疗法，这可能特别重要，因为越来越多的细菌菌株对传统抗生素治疗具有耐药性。

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.