Mycoplasma Polysaccharides and Control of Infection

支原体多糖与感染控制

• 批准号: 8532448
• 负责人: KEVIN F DYBVIG
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-21 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532448
• 关键词: ATP-Binding Cassette Transporters; Acetylglucosamine; Address; Animal Model; Animals; Antibiotic Therapy; Antigens; Asthma; Bacteria; Binding; Cell Wall; Cells; Chronic Disease; Code; Communities; Complement; Development; Disaccharides; Disease; Electron Microscopy; Encephalitis; Enzymes; Galactans; Galactose; Genes; Genital system; Genome; Glass; Glucose; Glycolipids; Glycosyltransferase Gene; Goals; Hamsters; Host Defense; Human; In Vitro; Infection; Infection Control; Joints; Lead; Learning; Lipids; Lung; Measures; Membrane; Meningitis; Methods; Microbial Biofilms; Modeling; Mollicutes; Mus; Mycoplasma; Mycoplasma gallisepticum; Mycoplasma mycoides; Mycoplasma pneumoniae; Mycoplasma pulmonis; Organism; Oryctolagus cuniculus; Pathogenesis; Pathologic; Pathway interactions; Plastics; Play; Pneumonia; Polysaccharides; Production; Proteins; Rattus; Reaction; Reporting; Research; Resistance; Role; Serum; Surface; Trachea; Translating; Uridine Diphosphate Galactose; Uridine Diphosphate Glucose; Virulence Factors; Work; antimicrobial; antimicrobial peptide; capsule; economic impact; epimerase; evidence base; gene cloning; genome sequencing; glycosyltransferase; in vivo; mutant; novel; pathogen; prevent; respiratory; sugar; sugar nucleotide; therapeutic target; vaccine development

DESCRIPTION (provided by applicant): Mycoplasma pneumoniae is the most significant of the mycoplasmal human pathogens, causing 20% to 30% of all community-acquired pneumonia. Even in mild cases, the economic impact of infection is considerable due to disease chronicity and associated loss of work. Serious extrapulmonary complications are not uncommon and include encephalitis and meningitis. The organism may also play a role in the pathogenesis of asthma. Mycoplasma pulmonis is a natural pathogen of rats and mice, the causative agent of murine respiratory mycoplasmosis (MRM). MRM shares many pathologic features with M. pneumoniae infection and is by far the best-characterized animal model of mycoplasmal disease. We believe that M. pulmonis and M. pneumoniae both produce at least two polysaccharides that are critical for pathogenesis. One of the polysaccharides may be capsular and the other required for a biofilm that can form in vivo and confer resistance to host defenses and antibiotic therapy. Although they have been virtually ignored by the field of mycoplasmology for the past 30 years, polysaccharides likely contribute to the pathogenesis and chronicity of disease as they do for most pulmonary bacterial pathogens. As such, the polysaccharides or the machinery that produces them, are potential therapeutic targets. The production of polysaccharides by these organisms is perhaps surprising because genome annotations identify very few genes with a potential role in polysaccharide synthesis. Mutants of M. pulmonis that fail to produce the polysaccharide EPS-I or the polysaccharide EPS-II have been identified and have transposon disruptions in genes that resemble ABC transporters and not conventional polysaccharide synthesis machinery. Polysaccharide synthesis in M. pulmonis may be novel and additional evidence suggests that the substrate for synthesis may be something other than nucleotide sugars. Whether polysaccharide synthesis in M. pneumoniae is similar to that of M. pulmonis remains to be determined. Aim 1 of this proposal is to further study polysaccharide synthesis in M. pulmonis through the characterization of existing mutants and the isolation of additional mutants. The goal is to identify the glycosyltransferases and substrates used for polysaccharide synthesis. One approach is to identify the substrates, and/or the intermediates in the pathway of substrate synthesis, that are missing or overproduced in the mutants. A second approach is to identify reaction conditions that support polysaccharide synthesis in vitro. A third is to clone the genes required for polysaccharide synthesis into other bacteria for study. Aim 2 is to translate what is learned in M. pulmonis to M. pneumoniae. Mutants of M. pneumoniae that fail to produce one or more polysaccharides will be isolated and studied as described for aim 1. The completion of these aims will have a major impact by establishing mycoplasmal polysaccharides as virulence factors and targets for control of infection.

描述（由申请方提供）：肺炎支原体是最重要的人类支原体病原体，引起20%-30%的社区获得性肺炎。即使在轻微的病例中，由于疾病的慢性化和相关的失业，感染的经济影响也是相当大的。严重的肺外并发症并不少见，包括脑炎和脑膜炎。该生物体也可能在哮喘的发病机制中发挥作用。肺支原体（Mycoplasma pulmonis）是大鼠和小鼠的一种自然病原体，是小鼠呼吸道支原体病（MRM）的病原体。MRM与M有许多共同的病理特征。pneumoniae感染，并且是迄今为止最具特征的支原体疾病动物模型。我们认为M。pulmonis和M.肺炎克雷伯氏菌和肺炎克雷伯氏菌都产生至少两种对发病机理至关重要的多糖。其中一种多糖可以是荚膜的，另一种多糖是生物膜所需的，生物膜可以在体内形成并赋予对宿主防御和抗生素治疗的抗性。尽管在过去的30年里，它们几乎被支原体学领域所忽视，但多糖可能有助于疾病的发病机制和慢性化，就像它们对大多数肺部细菌病原体所做的那样。因此，多糖或产生它们的机制是潜在的治疗靶点。这些生物体产生多糖可能是令人惊讶的，因为基因组注释识别出非常少的在多糖合成中具有潜在作用的基因。突变体M.已经鉴定了不能产生多糖EPS-I或多糖EPS-II的肺杆菌，并且在类似ABC转运蛋白而不是常规多糖合成机制的基因中具有转座子破坏。M.肺结核可能是新的，另外的证据表明，合成的底物可能是核苷酸糖以外的东西。M. pneumoniae与M.肺结核仍有待确定。目的一是进一步研究M.通过现有突变体的表征和另外的突变体的分离来研究肺结核。目的是鉴定用于多糖合成的糖基转移酶和底物。一种方法是鉴定在突变体中缺失或过度产生的底物和/或底物合成途径中的中间体。第二种方法是确定支持体外多糖合成的反应条件。第三种方法是将多糖合成所需的基因克隆到其他细菌中进行研究。目的二是翻译M中所学的内容。pulmonis为M.肺炎。突变体M.将不能产生一种或多种多糖的肺炎链球菌分离并如目的1所述进行研究。这些目标的完成将产生重大影响，建立支原体多糖作为毒力因子和控制感染的目标。