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: 8259059
• 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/8259059
• 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博士职务名称：粘液假单胞菌肺部感染的致病机制许多VA患者对机会致病菌铜绿假单胞菌的感染易感并死亡。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。暴露于这种无处不在的细菌可导致医院感染，这是常见的通过呼吸道呼吸机，导管，腰椎穿刺和普通外科手术。铜绿假单胞菌对大多数抗生素具有高度耐受性或耐药性，使得难以控制此类感染，从而导致高死亡率。本研究的目的是提高我们对一种称为藻酸盐的保护性囊状多糖的生物合成的理解，藻酸盐是铜绿假单胞菌产生的毒力因子。在慢性呼吸道感染期间（例如，COPD），体内适应性突变可导致该外泌多糖的过度产生，使得临床分离株表现出粘液样菌落形态。提高我们对铜绿假单胞菌致病机制的认识将加强对该细菌引起的肺部疾病的管理。大多数用于产生藻酸盐的酶聚集在12个基因的操纵子中。在这项研究中，我们将：（1）评估形成藻酸盐主要前体GDP-甘露糖醛酸盐的酶反应，（2）表征藻酸盐聚合和细胞质膜转移的机制，（3）表征藻酸盐乙酰化的机制，其赋予抗吞噬和厚生物膜性质，以及（4）与结构生物学家合作，确定海藻酸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组分的功能，海藻酸盐现在被认为是肺部感染期间的关键毒力因子。所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全面了解，这是细菌毒力避免宿主免疫反应的常见机制。 公共卫生关系： 相关性PI -丹尼斯E。Ohman博士职务名称：粘液假单胞菌肺部感染的致病机制铜绿假单胞菌感染是退伍军人中的一个重要问题。由于肺气肿、慢性支气管炎、COPD和其他疾病的并发症，许多VAMC患者容易受到铜绿假单胞菌的机会性感染。在使用呼吸道净化器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一个关键毒力因子是产生一种称为藻酸盐的胶囊状胞外多糖。更好地了解海藻酸盐生物合成中涉及的复杂机制可能会导致新的治疗方法。这项工作对VA卫生系统也很重要，因为假单胞菌感染由于其先天的抗生素耐药性而很难治疗。