Flagellin Stimulates Lung Innate Mucosal Immunity

描述（申请人提供）：细菌性肺炎是住院患者中一种常见且致命的并发症。铜绿假单胞菌（PA）是一种需氧革兰氏阴性细菌，是住院患者肺炎的第二大常见原因，由PA肺炎引起的机械通气肺炎的死亡率为60-90%。先天宿主对PA的应答是由选定的toll样受体（TLR）启动的，包括识别LPS的TLR4和被鞭毛蛋白激活的TLR5。鞭毛蛋白刺激对多种微生物病原体的保护性免疫，包括细菌和病毒。我们最近发现鞭毛蛋白是阳离子肽抗菌肽相关抗菌肽（CRAMP）的主要诱导剂。痉挛具有重要的杀菌和免疫调节特性，这可能有助于鞭毛蛋白在感染性和非感染性模型中观察到的保护作用。本修订建议的中心假设是鞭毛假单胞菌刺激保护性肺先天黏膜免疫，这部分是通过诱导阳离子抗菌肽CRAMP介导的。本建议的具体目标如下：确定阳离子抗菌肽CRAMP在PA肺炎特异性Aim 2期间粘膜先天反应中的作用。确定鞭毛蛋白诱导的肺保护性先天抗菌免疫刺激机制，这些研究将为抗菌肽在肺抗菌宿主防御中的作用提供重要的见解，并可能潜在地找到刺激肺粘膜免疫的新方法，可用于预防或治疗住院患者的肺炎。

DESCRIPTION (provided by applicant): Bacterial pneumonia is a frequent and deadly complication in hospitalized patients. Pseudomonas aeruginosa (PA) is an aerobic gram-negative bacterium that is the second most common cause of pneumonia in hospitalized patients, with mortality ranging from 60-90% in mechanically ventilated with pneumonia due to PA pneumonia. Innate host responses to PA are initiated by selected toll like receptors (TLR), including TLR4, which recognizes LPS, and TLR5, which is activated by flagellin. Flagellin stimulates protective immunity against diverse microbial pathogens, including bacteria and viruses. We have recently found that flagellin is a major inducer of the cationic peptide cathelicidin related antimicrobial peptide (CRAMP). CRAMP exerts important bactericidal and immunomodulatory properties that may contribute to the protective effects of flagellin observed in both infectious and non-infectious models. The central hypothesis of this revised proposal is that Pseudomonas flagellin stimulates protective lung innate mucosal immunity, which is mediated, in part, by the induction of the cationic antimicrobial peptide CRAMP. The Specific Aims of the proposal are as follows: Specific Aim 1. Determine the role of the cationic antimicrobial peptide CRAMP in mucosal innate responses during PA pneumonia Specific Aim 2. Determine the mechanism of flagellin-induced stimulation of protective lung innate antibacterial immunity The studies proposed will provide important insights into the role of cathelicidins in lung antibacterial host defense, and may potentially identify novel approaches to stimulate lung mucosal immunity that can be used to prevent or treat pneumonia in hospitalized patients. PUBLIC HEALTH RELEVANCE: Lung infection due to Pseudomonas aeruginosa continues to be a major cause of both morbidity and mortality in the United States. We have identified flagellin as a potent inducer of protective innate responses against this organism in experimental Pseudomonas pneumonia. Flagellin-induced protection is mediated, in part, by the antimicrobial peptide cathelicidin related antimicrobial peptide (CRAMP). The studies proposed in this application may identify novel means to prevent and possibly treat patients with respiratory tract infections due to P. aeruginosa.