Mechanisms of Mycoplasmal Disease Pathogenesis

支原体疾病发病机制

• 批准号: 7189109
• 负责人: KEVIN F DYBVIG
• 金额: $ 31.04万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7189109
• 关键词: Animal Model; Animals; Award; Bacterial Genome; Carbohydrates; Chronic Disease; Defect; Disease; Economics; Epithelium; Failure; Funding; Genes; Genetic; Genital system; Host Defense; Joints; Libraries; Life; Lung; Measures; Metabolism; Methods; Mus; Mycoplasma; Mycoplasma pulmonis; Nature; Nutrient; Organism; Pathogenesis; Regulation; System; carbohydrate transport; expectation; genome sequencing; in vivo; mutant; pathogen; respiratory; tool

DESCRIPTION (provided by applicant): Mycoplasmas are widely distributed in nature and commonly produce diseases of considerable economic impact, yet little information is available concerning mechanisms of pathogenesis and effective methods of control are unavailable. Mycoplasmal species have the smallest known bacterial genomes, and the availability of the genome sequence of at least 7 different species is being used as a measure for determining the minimal gene set for cellular life. But the mycoplasmas are dependent on the animal host to obtain many vital nutrients. The mycoplasmas not only have the tools to be self-replicating organisms, they also are fully equipped for survival in the animal and often cause chronic disease of the respiratory and genital tracts and joints. We propose to exploit mycoplasmas as minimalist systems for studying how pathogens acquire nutrients from their host and combat host defenses for long-term survival. We choose to use Mycoplasma pulmonis as a model organism because it is a natural pathogen of mice, causing murine respiratory mycoplasmosis. Thus, host-pathogen interactions can be explored using a minimalist pathogen and the power of mouse genetics. The expectation is that such studies will have broad impact for understanding host-dependent bacterial pathogens. For Specific Aim 1, we propose to study carbohydrate transport and metabolism. Little is known about mycoplasmal metabolism and its regulation. We believe that the ability to acquire carbohydrates from the animal host is of central importance for in vivo survival of the mycoplasma. During the funding period of the current award, a transposon library of M. pulmonis has been characterized to reveal mutants in nearly 300 genes. For Specific Aim 2, we propose to identify transposon mutants that fail to survive in the mouse lung. Mutants that do not survive will be characterized further to determine whether their defect is a failure to grow in vivo, to adhere to the epithelium, or to resist host defenses.

描述（由申请人提供）：支原体在自然界分布广泛，通常产生具有相当大经济影响的疾病，但关于其发病机制和有效控制方法的信息很少。支原体物种具有已知最小的细菌基因组，并且至少有7种不同物种的基因组序列可用性被用作确定细胞生命最小基因集的措施。但支原体依赖于动物宿主来获取许多重要的营养物质。支原体不仅拥有自我复制的工具，而且还具备在动物体内生存的全套装备，经常引起呼吸道、生殖道和关节的慢性疾病。我们建议利用支原体作为极简系统来研究病原体如何从宿主获取营养并对抗宿主防御以长期生存。我们选择肺支原体作为模型生物，因为它是小鼠的天然病原体，引起小鼠呼吸道支原体病。因此，宿主-病原体的相互作用可以利用极简病原体和小鼠遗传学的力量来探索。期望这样的研究将对理解寄主依赖性细菌病原体产生广泛的影响。对于Specific Aim 1，我们建议研究碳水化合物的运输和代谢。对支原体代谢及其调控知之甚少。我们认为，从动物宿主获得碳水化合物的能力对支原体在体内的生存至关重要。在本奖项资助期间，对肺支原体转座子文库进行了表征，揭示了近300个基因的突变。对于Specific Aim 2，我们建议鉴定无法在小鼠肺中存活的转座子突变体。不能存活的突变体将被进一步表征，以确定它们的缺陷是体内生长失败、粘附上皮失败还是抵抗宿主防御失败。