Microbial adaptation of Pseudomonas lipid A structure in CF airway disease progress

项目总结 持续性急性炎症和慢性感染是囊性纤维化(CF)肺部疾病的特征。 在CF患者的呼吸道中，细菌感染是造成大部分损害的原因。假性的慢性殖民 铜绿假单胞菌(PA)与疾病的进展和死亡密切相关，这是由于激活了 宿主的先天免疫系统。先天免疫细胞推动了这种强烈的炎症，但矛盾的是，它并没有 清除PA等病原体。我们以前已经证明，从CF儿童中分离出来的PA具有独特的 类脂A结构；最早适应于CF气道的结构之一。脂类A是脂质体的膜锚- 内毒素血症、局部组织破坏和感染性休克。另外-- 由于早期适应CF气道，一种高度促炎、超酰化的脂类A结构被观察到。 在从严重呼吸道疾病患者分离出来的大约三分之一的PA中服务。双环芳香烃的合成 作为炎症产物，特定的脂蛋白A结构在慢性肺疾病的发病机制中是必不可少的 从渗入的宿主免疫细胞，如中性粒细胞，需要PA在厚厚的 CF肺黏液含氧量低。这项提案的总体目标将加强和扩大我们的 假设在适应CF气道的过程中，Pa合成了改变宿主的CF特异性脂质A 先天免疫机制，导致慢性支气管炎的持续和慢性感染 中性粒细胞反应的调节可作为严重呼吸道疾病的控制机制。目标 在这项建议中，将首先确定确定的PA类脂A结构的致病性和信号潜力。 VANT小鼠模型和CF支气管上皮细胞系；第二，映射和分配促炎症因子的结构。 用质谱学方法研究肺脏病变过程中脂质A的积累和分布 成像。通过定义PA类脂A的结构如何调节宿主的持久性，我们将识别新的宿主-- 定向治疗(HDT)靶点。

PROJECT SUMMARY Persistent acute inflammation and chronic infection are hallmarks of Cystic Fibrosis (CF) pulmonary disease. Bacterial infections cause much of the damage seen in CF patients’ airways. Chronic colonization by Pseudo- monas aeruginosa (Pa) is strongly associated with disease progression and mortality due to the activation of the host innate immune system. Innate immune cells drive this strong inflammation but paradoxically fail to clear pathogens such as Pa. We have previously shown that Pa isolated from children with CF have unique lipid A structures; one of the earliest adaptations to the CF airway. Lipid A is the membrane anchor of lipopoly- saccharide (LPS) and is responsible for endotoxemia, localized tissue destruction, and septic shock. In addi- tion to early adaptation to the CF airway, a highly pro-inflammatory, hyper-acylated lipid A structure is ob- served in approximately one third of Pa isolated from patients with severe airway disease. The synthesis of specific lipid A structures is essential to CF lung disease pathogenesis as products of inflammation, derived from infiltrating host immune cells, such as neutrophils, are required for Pa to grow anaerobically in the thick and poorly oxygenated mucus of the CF lung. The overall goals of this proposal will strengthen and extend our hypothesis that during adaptation to the CF airway, Pa synthesizes CF-specific lipid A that alters host innate immune mechanisms, leading to persistence and chronic infection of the CF airways and that regulation of the neutrophil response could serve as a control mechanism for severe airway disease. The aims in this proposal will first, determine pathogenicity and signaling potential of defined Pa lipid A structures in rele- vant mouse models and CF bronchial epithelial cell lines and, second, map and assign structure to pro-inflam- matory Pa lipid A as it accumulates and distributes during the onset of lung pathology using mass spectrometry imaging. By defining how Pa lipid A structures condition the host for persistence, we will identify novel host- directed therapy (HDT) targets.