Pathogenic Mechanism for Lung Infection in Mucoid Pseudomonas

摘要 许多退伍军人症患者易受机会主义感染。 病原菌为铜绿假单胞菌。这可以作为慢性阻塞性肺疾病的并发症发生， 肺气肿、慢性支气管炎、癌症和免疫抑制药物治疗。暴露量 这种无处不在的细菌会导致医院感染，这是常见的通过 呼吸机、导尿管、腰椎穿刺术和普通外科手术。铜绿假单胞菌 对大多数抗生素具有高度耐受性或抗药性，因此很难控制 感染，这导致很高的发病率/死亡率。这项研究的目标是 为了提高我们对保护性胶囊的生物合成和调节的理解- 例如一种名为藻酸盐的多糖，它是由P. 铜绿假单胞菌。在慢性呼吸道感染(如COPD)期间，适应性突变是 观察到发生在体内，导致这种胞外多糖的过度生产， 这赋予了粘液集落表型和对吞噬细胞杀伤的抵抗力。这 表明在肺环境中生产藻酸盐有很高的选择压力。多数 产生海藻酸盐的酶的一半聚集在大的藻类D操纵子中。这个 粘液表型通常是由于激活sigma-22的突变所致。然而，我们有 发现了一种生产藻酸盐的替代途径，它涉及到一种2组分 调节子对(AlgB-KinB)和Sigma-54(RpoN)。此外，sigma-38(RpoN)也扮演着 在藻酸盐生产中的重要作用，但这一点还不清楚。改善我们的 了解铜绿假单胞菌的这一致病机制将有助于提高 这种细菌引起的肺部疾病的管理。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和(3) 确定增强粘液性假单胞菌吞噬功能的潜在药物 治疗剂。这项研究的长期目标是更好地了解藻酸盐 铜绿假单胞菌在肺部感染中作为关键毒力因子的产生。这个 所获得的信息可能对开发新的治疗方法至关重要 铜绿假单胞菌感染的治疗。

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.