Mechanisms of Mycoplasmal Disease Pathogenesis

支原体疾病发病机制

• 批准号: 6865025
• 负责人: KEVIN F DYBVIG
• 金额: $ 32.61万
• 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/6865025
• 关键词: Mycoplasma; bacteria infection mechanism; bacterial DNA; bacterial antigens; bacterial cytopathogenic effect; bacterial genetics; bacterial proteins; bactericidal immunity; carbohydrate metabolism; carbohydrate transport; gene expression; genetic polymorphism; genetic recombination; host organism interaction; laboratory mouse; mass spectrometry; matrix assisted laser desorption ionization; molecular pathology; nucleic acid sequence; phenotype; polymerase chain reaction; two dimensional gel electrophoresis; virulence

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）：支原体在自然界中广泛分布，通常会产生具有相当大经济影响的疾病，但有关致病机制的信息很少，也没有有效的控制方法。支原体物种具有最小的已知细菌基因组，并且至少7个不同物种的基因组序列的可用性被用作确定细胞生命的最小基因集的量度。但是支原体依赖于动物宿主来获得许多重要的营养物质。支原体不仅具有自我复制的工具，它们还完全具备在动物中生存的能力，并且经常导致呼吸道和生殖道以及关节的慢性疾病。我们建议利用支原体作为最低限度的系统，研究病原体如何从宿主获得营养物质，并对抗宿主的长期生存防御。我们选择使用肺支原体作为模式生物，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-病原体相互作用可以使用最低限度的病原体和小鼠遗传学的力量来探索。预期这些研究将对理解宿主依赖性细菌病原体产生广泛影响。对于具体目标1，我们建议研究碳水化合物的转运和代谢。关于支原体代谢及其调节知之甚少。我们相信从动物宿主获得碳水化合物的能力对于支原体的体内存活是至关重要的。 在本项目的资助期内，建立了M.肺结核的特征在于揭示了近300个基因中的突变体。对于特定目标2，我们建议鉴定在小鼠肺中不能存活的转座子突变体。将进一步表征不能存活的突变体，以确定它们的缺陷是不能在体内生长、不能粘附于上皮细胞还是不能抵抗宿主防御。