TLR4 and Pulmonary Innate Immunity to P.aeruginosa

TLR4 和肺对铜绿假单胞菌的先天免疫

• 批准号: 6442681
• 负责人: ADELINE M HAJJAR
• 金额: $ 30.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6442681
• 关键词: Pseudomonas aeruginosa; bacteria infection mechanism; bactericidal immunity; cystic fibrosis; gene targeting; genetically modified animals; inflammation; laboratory mouse; lipopolysaccharides; receptor; respiratory infections

DESCRIPTION (provided by applicant): Patients with cystic fibrosis (CF) develop persistent inflammation and chronic infections with Pseudomonas aeruginosa that ultimately result in their death. Toll-like receptors (TLRs) are type-I transmembrane proteins that transduce signals triggering the inflammatory and innate immune response to a variety of pathogens. TLR4, in concert with a co-receptor, MD-2, has been shown to mediate responses to lipopolysaccharide (LPS), a pro-inflammatory component of Gram-negative bacteria. This proposal will address the role that TLR4 plays in the pulmonary immune and inflammatory response to P. aeruginosa. The rationale for these studies derives from several novel observations made by our group. We have found that the structure of P. aeruginosa LPS isolated from CF patients is distinct from that of P. aeruginosa isolated from non-CF patients. Our preliminary in vitro data suggest that there are differences in the recognition of P. aeruginosa LPS by murine (mu) as compared to human (hu) TLR4. Specifically, muTLR4 mediates equivalent responses to both LPS from CF strains (CF-specific LPS) and non-CF strains (unmodified LPS) of P. aeruginosa, whereas huTLR4 responds much more poorly to non-CF than CF LPS. We hypothesize that CF LPS directly contributes to the chronic inflammation seen in CF and does so in part due to the unique recognition specificity of huTLR4, which recognizes and responds to CF LPS much more intensely than to unmodified LPS. The rapid and intense inflammatory response to P. aeruginosa in mouse lungs has limited the usefulness of mouse models for CF, possibly due to the more efficient recognition of unmodified LPS by muTLR4. We therefore propose to engineer a mouse that will mimic the decreased responsiveness of huTLR4 to unmodified LPS in order to evaluate the role that TLR4 plays in the immune response to P. aeruginosa.

描述（由申请人提供）： 囊性纤维化（CF）患者发生持续性炎症和慢性炎症。 感染铜绿假单胞菌，最终导致死亡。 Toll样受体（TLR）是一类跨膜蛋白， 触发炎症和先天免疫反应的信号， 病原体TLR 4与共受体MD-2一起，已经显示出 介导对脂多糖（LPS）的反应，脂多糖是一种促炎成分， 革兰氏阴性菌。该提案将阐述TLR 4所起的作用， 在肺部免疫和炎症反应中的作用。的 这些研究的基本原理来自于一些新的观察， 我们的团队我们已经发现分离的铜绿假单胞菌LPS的结构 从CF患者分离的铜绿假单胞菌与从非CF患者分离的铜绿假单胞菌不同 患者我们初步的体外实验数据表明， 与人（hu）相比，鼠（mu）对铜绿假单胞菌LPS的识别 TLR4。具体地，muTLR 4介导对来自CF的两种LPS的等效应答。 菌株（CF特异性LPS）和非CF菌株（未修饰的LPS）的P. 与铜绿假单胞菌相比，huTLR 4对非CF LPS的响应差得多，而huTLR 4对非CF LPS的响应差得多。 我们假设CF LPS直接参与慢性炎症 在CF中可见，部分原因是由于 huTLR 4，其识别和响应CF LPS比识别和响应CF LPS更强烈。 未修饰的LPS。对铜绿假单胞菌的快速而强烈的炎症反应 在小鼠肺中的作用限制了CF小鼠模型的有用性，可能是由于 通过muTLR 4更有效地识别未修饰的LPS。因此我们 我提议设计一种老鼠， 为了评估TLR 4在LPS刺激中所起的作用， 对铜绿假单胞菌的免疫反应。