Flagellin Stimulates Lung Innate Mucosal Immunity

描述(申请人提供)：细菌性肺炎是住院患者常见且致命的并发症。铜绿假单胞菌(PA)是一种革兰氏阴性杆菌，是住院患者肺炎的第二大致病菌，其病死率为60-90%。先天宿主对PA的反应是由选择的Toll样受体(TLR)启动的，包括识别内毒素的TLR4和被鞭毛蛋白激活的TLR5。鞭毛蛋白刺激对包括细菌和病毒在内的各种微生物病原体的保护性免疫。我们最近发现鞭毛蛋白是阳离子抗菌素相关抗菌肽(CRAMP)的主要诱导物。痉挛具有重要的杀菌和免疫调节作用，这可能有助于在感染和非感染模型中观察到鞭毛蛋白的保护作用。这一修订建议的中心假设是，鞭毛假单胞菌鞭毛蛋白刺激保护性肺固有粘膜免疫，这在一定程度上是通过诱导阳离子抗菌肽痉挛来介导的。本研究的具体目的如下：1.明确阳离子抗菌肽痉挛在肺炎期间粘膜先天反应中的作用2.明确鞭毛蛋白刺激保护性肺天然抗菌免疫的机制本研究将为天青素在肺抗菌宿主防御中的作用提供重要的见解，并有可能发现新的激发肺粘膜免疫的方法，可用于预防或治疗住院患者肺炎。 公共卫生相关性：铜绿假单胞菌引起的肺部感染仍然是美国发病率和死亡率的主要原因。我们已确定鞭毛蛋白是一种有效的诱导剂，可在实验性肺炎假单胞菌中诱导对这种微生物的天然保护性反应。鞭毛蛋白诱导的保护作用部分是由抗菌素相关抗菌肽(CRAMP)介导的。本申请中提出的研究可能确定预防和可能治疗由铜绿假单胞菌引起的呼吸道感染的新方法。

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.