Pathogenic Mechanism for Lung Infection in Mucoid Pseudomonas

粘液假单胞菌肺部感染的致病机制

• 批准号: 8394624
• 负责人: Dennis Edward Ohman
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394624
• 关键词: Acetylation; Acute Pneumonia; Alginates; Anabolism; Antibiotic Resistance; Antibiotics; Bacteremia; Bacteria; Bacterial Capsules; Burn injury; Cancer Patient; Catheters; Cell membrane; Cells; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Collaborations; Complex; Complication; Development; Disease; Doctor of Philosophy; Enzymes; Exposure to; Future; GDP mannuronate; Genes; Goals; Health system; Immune response; Immunosuppressive Agents; Infection; Knowledge; Lead; Life; Link; Lung; Lung diseases; Malignant Neoplasms; Membrane; Membrane Proteins; Microbial Biofilms; Modification; Molecular; Morphology; Multienzyme Complexes; Mutation; Nosocomial Infections; Occupational; Operative Surgical Procedures; Operon; Opportunistic Infections; Patients; Periplasmic Proteins; Phagocytosis; Pharmacotherapy; Pneumonia; Polymers; Polysaccharides; Process; Production; Properdin; Property; Proteins; Pseudomonas; Pseudomonas Infections; Pseudomonas aeruginosa; Pulmonary Emphysema; Reaction; Recombinant Proteins; Research; Resistance; Respiratory Tract Infections; Role; Spinal Puncture; Structural Biologist; Structure; Thick; Toxin; Ventilator; Veterans; Virulence; Virulence Factors; Work; antimicrobial drug; capsule; chemotherapy; cystic fibrosis patients; improved; in vivo; mortality; mucoid; new therapeutic target; novel; novel therapeutic intervention; pathogen; periplasm; polymerization; protein complex; respiratory; scaffold

DESCRIPTION (provided by applicant): ABSTRACT PI - Dennis E. Ohman, Ph.D. Title: Pathogenic Mechanism for Lung Infection in Mucoid Pseudomonas Many VA patients are susceptible and succumb to infections with the opportunistic pathogen, Pseudomonas aeruginosa. This can occur as a complication of emphysema, chronic bronchitis, cancer and immunosuppressive drug therapy. Exposure to this ubiquitous bacterium can result in nosocomial infections, which is common via respiratory ventilators, catheters, lumbar punctures and general surgery. P. aeruginosa is highly tolerant or resistant to most antibiotics, making it difficult to control such infections, which leads to a high mortality rate. The goal of this research is to improve our understanding of the biosynthesis of a protective capsule-like polysaccharide called alginate, which is produced as a virulence factor by P. aeruginosa. During chronic respiratory infections (e.g., COPD), adaptive mutations in vivo can lead to the over production of this exopolysaccharide such that clinical isolates demonstrate a mucoid colony morphology. Improving our understanding of this pathogenic mechanism in P. aeruginosa will enhance the management of pulmonary disease caused by this bacterium. Most of the enzymes for the production of alginate are clustered in an operon of 12 genes. In this study, we will: (1) evaluate the enzyme reactions in the formation of the main precursor of alginate, GDP-Mannuronate, (2) characterize the mechanism of alginate polymerization and cytoplasmic membrane transfer, (3) characterize the mechanism of alginate acetylation, which confers anti-phagocytic and thick biofilm properties, and (4) in collaboration with a structural biologist, determine the structures of alginate biosynthetic proteins to better understand the polymerization-secretion complex. The long-term goal of this research is to understand the functions of all of the components required for the biosynthesis of alginate, which is now recognized as a critical virulence factor during pulmonary infection. The information gained could be vital for the development of new therapeutic approaches in the treatment of P. aeruginosa infections. The results of these studies will also contribute to our overall understanding of bacterial capsule biosynthesis, which is a common mechanism of bacterial virulence for avoiding the host immune response.

描述（由申请人提供）： 摘要 PI - Dennis E. Ohman 博士标题：粘液假单胞菌肺部感染的致病机制 许多 VA 患者易感并死于机会性病原体铜绿假单胞菌感染。这可能是肺气肿、慢性支气管炎、癌症和免疫抑制药物治疗的并发症。接触这种普遍存在的细菌可能会导致医院感染，这种感染在呼吸机、导管、腰椎穿刺和普通手术中很常见。铜绿假单胞菌对大多数抗生素具有高度耐受性或耐药性，使得此类感染难以控制，从而导致高死亡率。这项研究的目的是提高我们对一种称为藻酸盐的保护性胶囊状多糖的生物合成的理解，这种多糖是由铜绿假单胞菌产生的毒力因子。在慢性呼吸道感染（例如慢性阻塞性肺病）期间，体内适应性突变可能导致这种胞外多糖的过量产生，从而使得临床分离株表现出粘液样集落形态。提高我们对铜绿假单胞菌致病机制的了解将加强对这种细菌引起的肺部疾病的治疗。大多数用于生产藻酸盐的酶都聚集在一个由 12 个基因组成的操纵子中。在本研究中，我们将：(1) 评估海藻酸盐主要前体 GDP-甘露糖醛酸形成过程中的酶反应，(2) 表征海藻酸盐聚合和细胞质膜转移的机制，(3) 表征海藻酸盐乙酰化的机制，赋予抗吞噬和厚生物膜特性，以及 (4) 与 结构生物学家，确定藻酸盐生物合成蛋白质的结构，以更好地了解聚合-分泌复合物。这项研究的长期目标是了解海藻酸盐生物合成所需的所有成分的功能，海藻酸盐现在被认为是肺部感染期间的关键毒力因子。获得的信息对于开发治疗铜绿假单胞菌感染的新治疗方法至关重要。这些研究的结果也将有助于我们对细菌荚膜生物合成的整体理解，这是细菌毒力避免宿主免疫反应的常见机制。