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: 10513284
• 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 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513284
• 关键词: Acetylation; Acute Pneumonia; Affect; Agar; Alginates; Anabolism; Antibiotic Resistance; Antibiotics; Antineoplastic Agents; Award; Bacteremia; Bacteria; Bacteria sigma factor KatF protein; Cancer Patient; Catheters; Cells; Chemicals; Chronic; Chronic Bronchitis; Chronic Obstructive Pulmonary Disease; Clinical; Complex; Complication; Cystic Fibrosis; Development; Disease; Effectiveness; Environment; Enzymes; Exposure to; Gene Expression; Genetic Transcription; Goals; Immune response; Immunosuppressive Agents; Infection; Knowledge; Life; Liquid substance; Lung; Lung diseases; Lung infections; Membrane; Microbial Biofilms; Modification; Molecular; Morbidity - disease rate; Morphology; Mutation; Nosocomial Infections; Occupational; Operative Surgical Procedures; Operon; Opportunistic Infections; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphorylation; Play; Pneumonia; Polymers; Polysaccharides; Positioning Attribute; Predisposition; Process; Production; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pulmonary Emphysema; Regulation; Research; Resistance; Respiratory Tract Infections; Role; Sigma Factor; Signal Transduction; Small RNA; Spinal Puncture; Stimulus; Stress; Therapeutic; Therapeutic Agents; Therapeutic Uses; Thick; Toxin; Untranslated RNA; Ventilator; Veterans; Virulence Factors; Work; antimicrobial drug; capsule; chemotherapy; derepression; gene product; improved; in vivo; mortality; mucoid; mutant; novel therapeutic intervention; novel therapeutics; opportunistic pathogen; pathogenic bacteria; polymerization; pressure; respiratory; small molecule libraries; transcriptome; transcriptome sequencing

ABSTRACT Many VA patients are susceptible and succumb to infections with the opportunistic pathogen, Pseudomonas aeruginosa. This can occur as a complication of COPD, emphysema, chronic bronchitis, cancer and immunosuppressive drug therapy. Exposure to this ubiquitous bacterium can result in nosocomial infections, which are 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 rate of morbidity/mortality. The goal of this research is to improve our understanding of the biosynthesis and regulation 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 are observed to occur in vivo that lead to the over production of this exopolysaccharide, which confers a mucoid colony phenotype and resistance to phagocytic killing. This suggests a high selective pressure for alginate production in the lung environment. Most of the enzymes for the production of alginate are clustered in the large algD operon. The mucoid phenotype is usually due to mutations that activate sigma-22. However, we have discovered an alternate pathway for alginate production that involves a 2-component regulator pair (AlgB-KinB) and sigma-54 (RpoN). Also, sigma-38 (RpoN) plays an important role in alginate production, but this is not understood. Improving our understanding of this pathogenic mechanism in P. aeruginosa will enhance the management of pulmonary disease caused by this bacterium. In this study, we will: (1) Determine the role of RpoN (sigma-54) in the control of alginate production, (2) Determine the role of RpoS (sigma-38) in the control of alginate production and (3) Identify drugs that enhance the phagocytosis of mucoid Pseudomonas as potential therapeutic agents. The long-term goal of this research is to better understand alginate production by P. aeruginosa 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.

摘要 许多VA患者是易感的，并死于机会性感染。 病原体，铜绿假单胞菌。这可能是COPD的并发症， 肺气肿、慢性支气管炎、癌症和免疫抑制药物治疗。暴露 这种无处不在的细菌可以导致医院感染，这是常见的，通过 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，使得难以控制这种 感染，导致发病率/死亡率高。本研究的目的是 来提高我们对保护性胶囊的生物合成和调节的理解- 比如一种叫做藻酸盐的多糖，它是由P. 铜绿。在慢性呼吸道感染期间（例如，适应性突变是 观察到在体内发生导致这种胞外多糖的过量产生， 其赋予粘液样集落表型和对吞噬杀伤的抗性。这 表明肺环境中藻酸盐产生的高选择压力。最 的用于产生藻酸盐的酶聚集在大的algD操纵子中。的 粘液样表型通常是由于激活σ-22的突变。但我们 发现了一种替代途径的海藻酸盐生产，涉及2-组分 调节子对（AlgB-KinB）和sigma-54（RpoN）。此外，sigma-38（RpoN）在 在藻酸盐生产中的重要作用，但这是不理解的。改善我们 了解铜绿假单胞菌的致病机制将有助于提高 管理由这种细菌引起的肺部疾病。在本研究中，我们将：（1） 确定RpoN（sigma-54）在控制藻酸盐生产中的作用，（2） 确定RpoS（sigma-38）在控制藻酸盐生产中的作用，以及（3） 确定增强粘液假单胞菌吞噬作用的药物作为潜在的 治疗剂。这项研究的长期目标是更好地了解海藻酸盐 铜绿假单胞菌的产生作为肺部感染期间的关键毒力因子。的 获得的信息对于开发新的治疗方法至关重要， 铜绿假单胞菌感染的治疗。