Revisiting alginate paradigms

重新审视藻酸盐范式

• 批准号: 10054154
• 负责人: Daniel J Wozniak
• 金额: $ 48.81万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-03 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054154
• 关键词: Alginates; Antimicrobial Resistance; Bacteria; Biochemical; Biochemical Genetics; Biology; Cells; Chronic; Clinical; Communities; Cystic Fibrosis; Data; Disease; Equilibrium; Genetic Diseases; Goals; Hypersensitivity; Immune response; Immunologics; Infection; Intervention; Knowledge; Lung diseases; Lung infections; Maintenance; Mediating; Microbial Biofilms; Molecular; Monitor; Mutation; Pathogenesis; Patients; Phenotype; Polysaccharides; Population; Prevalence; Production; Prognosis; Property; Proteins; Pseudomonas aeruginosa; Pulmonary Fibrosis; Reactive Oxygen Species; Research; Role; Structure; Testing; Translating; Variant; Virulence; antimicrobial; antimicrobial drug; chronic infection; cost; cystic fibrosis airway; cystic fibrosis infection; cystic fibrosis patients; effective therapy; experimental study; fitness; genetic approach; high risk; immunopathology; in vivo; infection risk; inflammatory milieu; member; microbial community; microbiota; mucoid; novel therapeutics; opportunistic pathogen; patient population; trait

Project Abstract This application seeks to define the molecular mechanisms and fitness benefits of alginate overproduction by mucoid variants of Pseudomonas aeruginosa. Specifically we will define features of the alginate biofilm matrix that enhance P. aeruginosa persistence and better understand the role of alginate in maintaining passive protection to the P. aeruginosa microbial community in the CF airway. This proposal will use state-of-the art molecular, biochemical, immunological, and genetic approaches to probe aspects of alginate pathogenesis and to reevaluate some long-standing paradigms. To date, the mechanisms underlying biofilm formation by alginate producing bacteria is not well understood. Aim 1 will investigate the biochemical and genetic basis for alginate biofilm matrix maintenance of biofilm integrity, structure, and antimicrobial resistance properties. While it is clear that mucoid variants predominate during chronic airway infection in CF patients, rarely are they present as pure clonal mucoid isolates. Instead, mucoid bacteria are typically associated with mixed populations of wild type P. aeruginosa that have not undergone mucoid conversion, as well as spontaneous suppressors that arise. The goal of Aim 2 is to test the hypothesis that this mixed consortia confers fitness benefits to the P. aeruginosa community as a whole that is not observed in either nonmucoid or mucoid bacteria alone. Alginate expression in the CF lung correlates with a poor clinical prognosis. However there are gaps in our knowledge regarding specific properties that alginate overproduction affords bacteria and the microbial consortia within the airway. The completion of these aims will lead to a deeper understanding of alginate biology and translate into novel therapies or interventions for CF patients colonized with mucoid P. aeruginosa.

项目摘要 本申请试图通过以下方式来定义藻酸盐过量生产的分子机制和适合性益处： 铜绿假单胞菌的粘液样变体。具体来说，我们将定义藻酸盐生物膜基质的特征 这增强了铜绿假单胞菌的持久性，并更好地理解了藻酸盐在维持被动 保护CF气道中的铜绿假单胞菌微生物群落。 该提案将使用最先进的分子，生物化学，免疫学和遗传学方法来探测 藻酸盐发病机制的各个方面，并重新评估一些长期存在的范例。迄今为止， 产生藻酸盐的细菌的潜在生物膜形成还没有被很好地理解。目标1将调查 藻酸盐生物膜基质的生物化学和遗传学基础维持生物膜的完整性，结构， 抗微生物抗性特性。虽然很明显，粘液变体在慢性气道炎症中占主导地位， 在CF患者中的感染中，它们很少以纯克隆粘液样分离物存在。相反，粘液细菌 典型地与未经历粘液样变性的野生型铜绿假单胞菌的混合群体相关， 转换，以及自发的抑制剂出现。目标2的目标是检验假设， 混合聚生体赋予铜绿假单胞菌群落作为一个整体的健身效益，这是在 非粘液或粘液细菌单独存在。CF肺中的藻酸盐表达与不良的临床表现相关， 预后然而，在我们的知识中，关于藻酸盐的特定性质， 过量生产在气道内提供细菌和微生物聚生体。这些目标的实现 将导致对藻酸盐生物学的更深入理解，并转化为CF的新疗法或干预措施 粘液型铜绿假单胞菌定植患者。