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: 6789299
• 负责人: ADELINE M HAJJAR
• 金额: $ 30.32万
• 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 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6789299
• 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) 患者会出现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 I 型跨膜蛋白，可转导 触发炎症和先天免疫反应的信号对多种 病原体。 TLR4 与辅助受体 MD-2 协同作用已被证明 介导对脂多糖（LPS）的反应，脂多糖是一种促炎成分 革兰氏阴性细菌。该提案将解决 TLR4 所扮演的角色 对铜绿假单胞菌的肺部免疫和炎症反应。这 这些研究的基本原理来自于一些新的观察结果 我们组。我们发现分离的铜绿假单胞菌LPS的结构 来自CF患者的铜绿假单胞菌与从非CF患者中分离的铜绿假单胞菌不同 患者。我们的初步体外数据表明，存在差异 与人类 (hu) 相比，小鼠 (mu) 对铜绿假单胞菌 LPS 的识别 TLR4。具体而言，muTLR4 介导 CF 中对两种 LPS 的等效反应 P. 菌株（CF 特异性 LPS）和非 CF 菌株（未修饰的 LPS）。 铜绿假单胞菌，而 huTLR4 对非 CF 的反应比对 CF LPS 的反应差得多。 我们假设 CF LPS 直接导致慢性炎症 在 CF 中看到，这样做的部分原因是 huTLR4，它对 CF LPS 的识别和反应比对 CF LPS 的识别和反应强烈得多 未修饰的LPS。对铜绿假单胞菌的快速而强烈的炎症反应 小鼠肺部的感染限制了小鼠 CF 模型的实用性，可能是由于 muTLR4 更有效地识别未修饰的 LPS。我们因此 建议设计一种能够模仿响应能力下降的鼠标 huTLR4 与未修饰的 LPS 结合，以评估 TLR4 在 对铜绿假单胞菌的免疫反应。