Pseudomonas aeruginosa lipid A

描述（由申请人提供）：囊性纤维化（CF）患者患有机会致病菌铜绿假单胞菌（PA）的慢性气道感染，并经历恶化，不可逆的肺损伤导致过早死亡。这种损伤是由炎症过程介导的，至少部分是由脂多糖（IPS）的生物活性成分PA脂质A刺激先天免疫系统引起的。CF患者分离的PA具有独特的结构修饰，可组成性合成脂质A。这些结构的合成可能对CF肺病的发病机制至关重要。具有独特脂质A的PA可通过两种方式促进CF肺病：通过增加宿主炎症反应，以及通过增加细菌对宿主先天免疫成分（如阳离子抗菌肽（camp）或抗生素）的耐药性。因此，我们建议通过鉴定参与脂质A合成的基因，构建无法合成特定脂质A结构的等基因PA突变菌株，并在肺部炎症模型中检测具有这些特定脂质A结构的PA及其对camp的易感性，来确定这些脂质A结构修饰与CF肺部疾病的相关性和调控。这些研究将有助于深入了解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肺感染及其炎症后果的药物提供新的靶点。

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.