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

项目摘要 持续的急性炎症和慢性感染是囊性纤维化（CF）肺病的标志。 细菌感染导致CF患者气道中的大部分损伤。慢性定植的伪- 铜绿假单胞菌（Pa）与疾病进展和死亡率密切相关， 宿主的先天免疫系统先天免疫细胞驱动这种强烈的炎症，但矛盾的是， 明确病原体，如Pa.我们以前已经证明，从CF儿童中分离出的Pa具有独特的 脂质A结构; CF气道的最早适应之一。脂质A是脂多糖的膜锚， 糖（LPS），并导致内毒素血症、局部组织破坏和败血性休克。此外- 为了早期适应CF气道，观察到高度促炎性、超酰化的脂质A结构， 在大约三分之一的严重气道疾病患者中分离出Pa。的合成 特定的脂质A结构是CF肺病发病机制所必需的，作为炎症产物， 从浸润宿主免疫细胞，如嗜中性粒细胞，需要Pa在厚的厌氧生长。 以及CF肺的含氧粘液不足。本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CF特异性脂质A， 先天免疫机制，导致CF气道的持续性和慢性感染， 中性粒细胞反应的调节可以作为严重气道疾病的控制机制。目标 在该提议中，将首先确定确定致病性和确定的Pa脂质A结构在rele中的信号传导潜力， vant小鼠模型和CF支气管上皮细胞系，第二，映射和分配结构，以pro-inflam- 使用质谱法测定炎性Pa脂质A在肺病理学发作期间的累积和分布 显像通过定义Pa脂质A结构如何调节宿主的持久性，我们将鉴定新的宿主- 定向治疗（HDT）的目标。

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.