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: 7927720
• 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/7927720
• 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. PUBLIC HEALTH RELEVANCE: Relevance PI - Dennis E. Ohman, Ph.D. Title: Pathogenic Mechanism for Lung Infection in Mucoid Pseudomonas Infection with the bacterium Pseudomonas aeruginosa is a significant problem among our veterans. Many VAMC patients are susceptible to opportunistic infections with P. aeruginosa due to complications with emphysema, chronic bronchitis, COPD and other disorders. Nosocomial infection during treatment with respiratory ventilators is also common. A key virulence factor of P. aeruginosa during pulmonary infection is the production of a capsule-like exopolysaccharide called alginate. A better understanding of the complex mechanisms involved in alginate biosynthesis could lead to novel therapies. This work is also of importance to the VA health system because Pseudomonas infections are very difficult to treat due to its innate antibiotic resistance.

描述（由申请人提供）： 摘要Pi -Dennis E. Ohman，博士标题：粘液假单胞菌中肺部感染的致病机制许多VA患者敏感并屈服于机会性病原体铜绿假单胞菌。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。暴露于这种普遍的细菌会导致医院感染，这是通过呼吸道呼吸机，导管，腰椎穿刺和一般手术常见的。铜绿假单胞菌对大多数抗生素具有很高的耐受性或抗性，因此难以控制这种感染，从而导致高死亡率。这项研究的目的是提高我们对称为藻酸盐的保护性胶囊样多糖的生物合成的理解，该多糖被铜绿假单胞菌作为毒力因子产生。在慢性呼吸道感染（例如COPD）期间，体内适应性突变会导致这种外多糖的过度产生，从而使临床分离株表现出粘液菌落形态。提高我们对铜绿假单胞菌病原机制的理解将增强该细菌引起的肺疾病的治疗。生产藻酸盐的大多数酶都聚集在12个基因的操纵子中。在这项研究中，我们将：（1）评估藻酸盐主要前体GDP-甘露元酸酯的形成中的酶反应（2）表征了藻酸盐聚合和细胞质膜转移的机制（3）（3）在藻酸盐的机制中表征了Acety acety ant-phagofficy and-phagofoffofofoffiel，抗磷酸的机制，抗磷脂（4）结构生物学家，确定藻酸盐生物合成蛋白的结构，以更好地了解聚合分泌络合物。这项研究的长期目标是了解藻酸盐生物合成所需的所有组成部分的功能，藻酸盐的生物合成所需的所有成分，现在被认为是肺部感染过程中的临界毒力因子。获得的信息对于在治疗铜绿假单胞菌感染中开发新的治疗方法可能至关重要。这些研究的结果还将有助于我们对细菌胶囊生物合成的总体理解，这是避免宿主免疫反应的细菌毒力的常见机制。 公共卫生相关性： 相关性PI -Dennis E. Ohman博士标题：在铜绿细菌铜绿铜中感染肺假单胞菌中肺部感染的致病机制是我们退伍军人中的一个重要问题。由于肺气肿，慢性支气管炎，COPD和其他疾病并发症，许多VAMC患者易受机会性的铜绿假单胞菌感染。呼吸道通风剂治疗期间的医院感染也很常见。铜绿假单胞菌在肺部感染过程中的关键毒力因子是生产称为藻酸盐的胶囊样外多糖。更好地了解藻酸盐生物合成所涉及的复杂机制可能会导致新的疗法。这项工作对于VA卫生系统也很重要，因为假单胞菌感染由于其先天抗生素的耐药性而难以治疗。