The pel exopolysaccharide gene cluster of Pseudomonas aeruginosa

铜绿假单胞菌胞外多糖基因簇

• 批准号: 9102865
• 负责人: MATTHEW R. PARSEK
• 金额: $ 48.91万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102865
• 关键词: Accounting; Address; Amino Sugars; Anabolism; Animal Model; Antibiotics; Bacteria; Biological Assay; Chemicals; Chronic; Clinical; Communities; Cystic Fibrosis; Data; Development; Disease; Environment; Exhibits; Extracellular Matrix; Family suidae; Feedback; Future; Gene Cluster; Genes; Genetic; Genotype; Goals; Health; Host Defense; Human; In Vitro; Individual; Infection; Intervention; Knowledge; Lead; Link; Microbial Biofilms; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Pathogenesis; Pathway interactions; Phenotype; Polysaccharides; Predisposition; Prevalence; Production; Pseudomonas aeruginosa; Quality of life; Role; Signal Transduction; Structure; Surveys; Therapeutic; Therapeutic Agents; Variant; antimicrobial; base; cystic fibrosis airway; cystic fibrosis patients; fitness; genetic approach; genetic variant; improved; mortality; mucoid; mutant; neutrophil; novel; oligoribonuclease; outcome forecast; phosphoric diester hydrolase; research study; sugar; trait

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa infections result in significant morbidity and mortality in people suffering from cystic fibrosis (CF). A key feature of these infections is that they involve biofilm communities. Another is that during the course of chronic infection, P. aeruginosa acquires mutations that help it adapt to the CF environment. This proposal will investigate a clear link between biofilm formation and genetic adaptation, the RSCV phenotype. RSCVs generally exhibit increased biofilm formation and antimicrobial tolerance relative to the non- mucoid, smooth colony morphotype. One important trait of RSCVs are elevated production of the biofilm matrix exopolysaccharide PEL. The structure of PEL remains unknown, and its elucidation is a goal of this proposal. In addition, P. aeruginosa RSCVs are actively selected for during the course of chronic cystic fibrosis (CF) airway infections. We recently discovered that the prevalence of RSCVs in the CF airways has been grossly underestimated and we subsequently identified novel genetic loci linked to the RSCV phenotype. The molecular mechanism underpinning why these mutations produce RSCVs is unclear. Finally, we found that RSCVs can be highly variable phenotypically, depending upon the causal mutation. Some of these variable phenotypes are pathogenically relevant, suggesting that different RSCVs may vary in their ability to form biofilms and cause chronic infection. The overall goals of this application are to determine the structure of PEL and to elucidate the molecular mechanism leading to the RSCV phenotype that results from novel RSCV- linked mutations. We will also examine the pathogenic fitness advantages of different RSCV genotypes using chronic animal models of infection and in vitro cellular immunological assays. Once mucoid genetic variants of P. aeruginosa emerge, prognosis of CF patients clearly worsens. Thus, there exists a critical window of opportunity for immunological or chemotherapeutic intervention prior to mucoid conversion. RSCVs are usually observed prior to mucoidy, thus therapeutic strategies taking advantage of this window of opportunity would have to account for them. A thorough analysis of RSCVs and Pel may lead to the development of therapeutic agents and improve the quality of life for CF patients as well as individuals with other P. aeruginosa infections that involve biofilms.

描述（由申请人提供）：铜绿假单胞菌感染导致囊性纤维化（CF）患者显着发病和死亡。一个关键特征是 这些感染的特点是它们涉及生物膜群落。另一个原因是，在慢性感染过程中，铜绿假单胞菌会发生突变，帮助其适应 CF 环境。该提案将研究生物膜形成与遗传适应（RSCV 表型）之间的明确联系。相对于非粘液、光滑的集落形态类型，RSCV 通常表现出增加的生物膜形成和抗菌耐受性。 RSCV 的一项重要特征是生物膜基质胞外多糖 PEL 的产量增加。 PEL 的结构仍然未知，其阐明是本提案的目标。此外，在慢性囊性纤维化（CF）气道感染过程中，铜绿假单胞菌RSCV被积极选择。我们最近发现 CF 气道中 RSCV 的患病率被严重低估，随后我们发现了与 RSCV 表型相关的新基因位点。这些突变产生 RSCV 的分子机制尚不清楚。最后，我们发现 RSCV 在表型上可能存在高度可变性，具体取决于因果突变。其中一些可变表型与致病相关，表明不同的 RSCV 形成生物膜和引起慢性感染的能力可能有所不同。本申请的总体目标是确定 PEL 的结构并阐明导致新 RSCV 连锁突变产生 RSCV 表型的分子机制。我们还将使用慢性动物感染模型和体外细胞免疫测定来检查不同 RSCV 基因型的致病适应性优势。一旦铜绿假单胞菌的粘液样遗传变异出现，CF患者的预后明显恶化。因此，在粘液转化之前存在免疫或化疗干预的关键机会窗口。 RSCV 通常在粘液形成之前观察到，因此利用这一机会窗口的治疗策略必须考虑到它们。对 RSCV 和 Pel 的彻底分析可能会导致治疗药物的开发，并改善 CF 患者以及涉及生物膜的其他铜绿假单胞菌感染的个体的生活质量。