Pseudomonas aeruginosa lipid A

描述（由申请人提供）：囊性纤维化（CF）患者患有机会性病原体铜绿假单胞菌（PA）的慢性气道感染，并出现恶化的不可逆肺损伤，导致过早死亡。这种损伤是由炎症过程介导的，该炎症过程至少部分地由PA脂质A（脂多糖（IPS）的生物活性组分）刺激先天免疫系统引起。从CF患者分离的PA组成型合成具有独特结构修饰的脂质A。这些结构的合成可能是CF肺病发病机制所必需的。PA与独特的脂质A可能有助于CF肺疾病在两个方面：通过增加宿主的炎症反应，并通过增加细菌耐宿主先天免疫的元素，如阳离子抗菌肽（CAMP）或抗生素。因此，我们建议确定的相关性和调节这些脂质A的结构修饰CF肺部疾病，通过确定参与其合成的基因，构建同基因PA突变株无法合成特定的脂质A的结构，并测试PA与这些特定的脂质A的结构模型中的肺部炎症和他们的易感性CAMPs。这些研究将深入了解导致CF肺病的细菌机制，包括脂质A修饰酶的作用。这些酶可能为开发治疗PA肺部感染及其炎症后果的药物提供新的靶点。 该提案的重点是进一步定义合成和调节囊性纤维化特异性脂质A所需的酶，脂质A是各种铜绿假单胞菌临床分离背景中脂多糖的生物活性组分。从囊性纤维化患者分离的铜绿假单胞菌组成型合成具有独特结构修饰的脂质A。此外，将确定特定的脂质A结构在调节宿主先天免疫系统和炎症反应中的作用。这些研究可能导致鉴定出阻断CF特异性脂质A结构的合成并使铜绿假单胞菌对宿主细胞杀伤和/或常规抗生素干预更敏感的候选蛋白质靶标。

DESCRIPTION (provided by applicant): Patients with cystic fibrosis, (CF) suffer from chronic airway infections with the opportunistic pathogen Pseudomonas aeruginosa (PA), and experience worsening, irreversible lung injury leading to premature death. This injury is mediated by an inflammatory process that results, at least in part, from stimulation of the innate immune system by PA lipid A, the bioactive component of lipopolysaccharide (IPS). PA isolates from CF patients constitutively synthesize lipid A with unique structural modifications. The synthesis of these structures may be essential for CF lung disease pathogenesis. PA with unique lipid A could contribute to CF lung disease in two ways: by increasing host inflammatory responses, and by increasing bacterial resistance to elements of host innate immunity, such as cationic antimicrobial peptides (CAMPs) or antibiotics. We therefore propose to identify the relevance and regulation of these lipid A structural modifications to CF pulmonary disease by identifying genes involved in their synthesis, constructing isogenic PA mutant strains unable to synthesize specific lipid A structures, and testing PA with these specific lipid A structures in models of lung inflammation and their susceptibility to CAMPs. These studies will provide insight into bacterial mechanisms that contribute to CF lung disease, including the role of lipid A modifying enzymes. Such enzymes may provide novel targets for the development of drugs to treat PA lung infections and their inflammatory consequences. The focus of this proposal is to further define enzymes required for the synthesis and regulation of cystic fibrosis-specific lipid A, the bioactive component of lipopolysaccharide in a variety of Pseudomonas aeruginosa clinical isolate backgrounds. P. aeruginosa isolates from patients with cystic fibrosis constitutively synthesize lipid A with unique structural modifications. In addition, the role of specific lipid A structures in modulation of the host the innate immune system and inflammatory responses will be determined. These studies could lead to the identification of candidate protein targets that block the synthesis of CF-specific lipid A structures and render P. aeruginosa more susceptible to host cell killing and/or conventional antibiotic intervention.