TLR4 and Pulmonary Innate Immunity to P.aeruginosa

描述(由申请人提供)： 囊性纤维化患者发展为持续性炎症和慢性 感染铜绿假单胞菌，最终导致死亡。 Toll样受体(TLRs)是一种I型跨膜蛋白。 触发炎症和先天免疫反应的信号 病原体。TLR4与辅助受体MD-2协同作用已被证明 介导对内毒素(LPS)的反应，内毒素是一种促炎症成分 革兰氏阴性细菌。该提案将解决TLR4所扮演的角色 在肺部对铜绿假单胞菌的免疫和炎症反应。这个 这些研究的理论基础来自以下几个新的观察结果 我们这群人。我们发现分离的铜绿假单胞菌内毒素的结构 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 病人。我们的初步体外数据表明，在 小鼠(MU)与人(HU)对铜绿假单胞菌内毒素的识别 TLR4.具体地说，muTLR4介导Cf对两种脂多糖的同等反应 卡介苗(P.) 铜绿假单胞菌，而huTLR4对非CFLR4的反应要比CFLPS差得多。 我们推测CFLPS直接参与了慢性炎症。 在CF中可以看到，这在一定程度上是由于 HuTLR4，它对CFLPS的识别和响应比对 未经修饰的脂多糖。铜绿假单胞菌快速而强烈的炎症反应 在小鼠肺中的作用限制了小鼠模型对CF的有用性，可能是由于 从而提高了muTLR4对未修饰内毒素的识别效率。因此，我们 建议设计一种鼠标来模拟降低的响应速度 HuTLR4与未修饰的内毒素结合，以评估TLR4在 铜绿假单胞菌的免疫应答。

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.