Tandemly Repetitive Proteins in Mycoplasmas

支原体中的串联重复蛋白

• 批准号: 7154096
• 负责人: KEVIN F DYBVIG
• 金额: $ 31.79万
• 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: 2005-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154096
• 关键词: Affect; Alveolar Macrophages; Antigens; Appendix; Bacterial Pneumonia; C-terminal; Cell Wall; Cell surface; Cells; Complement; Complement Component Protein; Complement Membrane Attack Complex; Complex; Cytolysis; Deposition; Digestion; Disease; Distal; Economics; Electron Microscopy; Enzymes; Extracellular Matrix; Family; Family member; Frequencies; Gene Family; Genes; Genetic Variation; Genome; Goals; Growth; Hemadsorption; Human; Immunocompetent; Individual; Infection Control; Label; Length; Lesion; Lipids; Lipoproteins; Lung; Lung diseases; Malaria; Manuscripts; Measures; Membrane; Membrane Proteins; Methods; Microbe; Modeling; Modification; Mus; Mycoplasma; Mycoplasma pulmonis; Numbers; Organelles; Parasites; Pathogenesis; Phagocytosis; Phase; Predisposition; Process; Production; Property; Proteins; Public Health; Radiolabeled; Range; Rattus; Relative (related person); Research Personnel; Resistance; Role; Severities; Site; Sodium Chloride; Solutions; Structure; Study models; Surface; Surface Antigens; System; Tandem Repeat Sequences; Thick; Thinking; Trypsin; Tuberculosis; Variant; Virulence; capsule; cell type; complement C3 precursor; extracellular; improved; insight; member; microbial; pathogen; programs; radiotracer; respiratory; size

DESCRIPTION (provided by applicant): Mycoplasmas commonly produce diseases of considerable economic impact, yet little information is available concerning mechanisms of pathogenesis and effective methods of control are unavailable. Many mycoplasmas possess surface proteins with regions of identical tandem repeats, sometimes with 40 or more repeat units per protein. Such molecules are usually lipoproteins with the lipid moiety serving to anchor the protein to the membrane and the carboxyl tandem repeat region free to interact with host cells and molecules. These proteins are all subject to high-frequency size variation due to slipped-strand mispairing that result in gain or loss of repeat units. The functions of these repetitive proteins and the phenotypic consequences of size variation are unknown. In the murine pathogen Mycoplasma pulmonis, size variation in the Vsa proteins modulates the growth properties of the mycoplasma (colony size variation), hemadsorption, and susceptibility to complement lysis. Our long-range goals are to understand the pathogenic mechanisms of mycoplasmas. The goal of the current proposal is to study the functions and pathogenic significance of Vsa size variation. Many mycoplasmas including M. pulmonis possess an extracellular matrix. We propose that this matrix is composed of the Vsa proteins and serves to protect the mycoplasma from complement. Aim 1 is to examine the matrix by electron microscopy, to determine if it is composed of the Vsa proteins, and to determine whether it is a barrier to complement. The Vsa proteins may affect interactions between the mycoplasma and host cells, and whether Vsa modulates the susceptibility of the mycoplasma to phagocytosis will be examined in Aim 2. In Aim 3, the pathogenic significance of Vsa size variation will be studied by comparing the ability of cells that produce a large (many tandem repeats) or a small (few repeats) Vsa protein in respect to their ability to colonize and cause disease in immuno-competent and complement deficient mice. The results of these studies will elucidate the role of highly repetitive proteins in mycoplasmal diseases. They will also provide insight into the functions of repetitive proteins in other microbes that are important to public health including the agents responsible for malaria, tuberculosis, and a variety of bacterial pneumonias. By understanding the role of repetitive proteins in the disease process, it is anticipated that improved measures to control the infections of these significant human pathogens will be developed.

描述（由申请人提供）：支原体通常会产生具有相当大经济影响的疾病，但有关发病机制的信息很少，并且没有有效的控制方法。许多支原体拥有具有相同串联重复区域的表面蛋白，有时每个蛋白具有 40 个或更多重复单元。此类分子通常是脂蛋白，其中脂质部分用于将蛋白质锚定到膜上，并且羧基串联重复区域自由地与宿主细胞和分子相互作用。由于滑链错配，这些蛋白质都会遭受高频大小变化，从而导致重复单元的增加或丢失。这些重复蛋白质的功能和大小变异的表型后果尚不清楚。在鼠类病原体肺支原体中，Vsa 蛋白的大小变化可调节支原体的生长特性（菌落大小变化）、血细胞吸附和补体裂解的敏感性。我们的长期目标是了解支原体的致病机制。当前提案的目标是研究 Vsa 大小变异的功能和致病意义。许多支原体，包括肺支原体，都具有细胞外基质。我们认为该基质由 Vsa 蛋白组成，可保护支原体免受补体侵害。目标 1 是通过电子显微镜检查基质，确定其是否由 Vsa 蛋白组成，并确定其是否是补体屏障。 Vsa蛋白可能影响支原体和宿主细胞之间的相互作用，目标2将研究Vsa是否调节支原体对吞噬作用的敏感性。目标3将通过比较Vsa大小变异的能力来研究Vsa大小变异的致病意义。产生大（许多串联重复）或小（少量重复）Vsa 蛋白的细胞，就其在免疫活性和补体中定殖和引起疾病的能力而言缺乏的老鼠。这些研究的结果将阐明高度重复蛋白在支原体疾病中的作用。他们还将深入了解其他微生物中重复蛋白的功能，这些微生物对公共卫生很重要，包括导致疟疾、结核病和各种细菌性肺炎的病原体。通过了解重复蛋白在疾病过程中的作用，预计将开发出控制这些重要人类病原体感染的改进措施。