Flagellin Stimulates Lung Innate Mucosal Immunity

鞭毛蛋白刺激肺先天粘膜免疫

• 批准号: 8212532
• 负责人: Theodore J. Standiford
• 金额: $ 41.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212532
• 关键词: Alveolar; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacteria; Bacterial Pneumonia; Cells; Complication; Data; Distant; Epithelial; Epithelial Cells; Flagellin; Gram-Negative Aerobic Bacteria; Host Defense; Immune response; Immunity; Infection; Intranasal Administration; Lung; Mediating; Modeling; Morbidity - disease rate; Mucosal Immunity; Mus; Myeloid Cells; Nanotechnology; Natural Immunity; Organism; Outcome; Patients; Peptides; Pneumonia; Property; Pseudomonas; Pseudomonas aeruginosa; Receptor Signaling; Relative (related person); Respiratory Tract Infections; Role; Signal Pathway; Site; TLR4 gene; TLR5 gene; Toll-like receptors; United States; Virus; alveolar epithelium; antimicrobial peptide; bactericide; cathelicidin; cathelicidin antimicrobial peptide; insight; macrophage; microbial; mortality; novel; novel strategies; pathogen; prevent; protective effect; public health relevance; research study; response

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.

描述（由申请人提供）：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）是一种需氧革兰氏阴性细菌，是住院患者肺炎的第二大常见原因，在机械通气的PA肺炎患者中，死亡率为60-90%。对PA的先天宿主应答由选择的Toll样受体（TLR）启动，包括识别LPS的TLR 4和由鞭毛蛋白激活的TLR 5。鞭毛蛋白刺激针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抗菌肽cathelicidin相关抗菌肽（CRAMP）的主要诱导物。CRAMP发挥重要的杀菌和免疫调节特性，这可能有助于在感染性和非感染性模型中观察到的鞭毛蛋白的保护作用。该修订提案的中心假设是假单胞菌鞭毛蛋白刺激保护性肺先天粘膜免疫，其部分由阳离子抗菌肽CRAMP的诱导介导。该提案的具体目标如下：具体目标1。确定阳离子抗菌肽CRAMP在PA肺炎特异性目标2期间的粘膜先天性反应中的作用。确定鞭毛蛋白诱导的刺激保护性肺先天抗菌免疫的机制所提出的研究将为cathelicidins在肺抗菌宿主防御中的作用提供重要的见解，并可能确定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。 公共卫生相关性：在美国，由铜绿假单胞菌引起的肺部感染仍然是发病率和死亡率的主要原因。我们已经确定鞭毛蛋白作为一种有效的诱导剂的保护性先天反应，对这种生物体在实验假单胞菌肺炎。鞭毛蛋白诱导的保护作用部分由抗菌肽凯萨林菌素相关抗菌肽（CRAMP）介导。本申请中提出的研究可以确定预防和可能治疗铜绿假单胞菌所致呼吸道感染患者的新方法。