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

点击翻译按钮获取中文摘要

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.