Tandemly Repetitive Proteins in Mycoplasmas

描述（由申请人提供）：支原体通常产生具有相当大经济影响的疾病，但关于发病机制的信息很少，也没有有效的控制方法。许多支原体的表面蛋白具有相同的串联重复序列，有时每个蛋白质有40个或更多的重复单位。这样的分子通常是脂蛋白，其脂质部分用于将蛋白质锚在膜上，羧基串联重复区自由地与宿主细胞和分子相互作用。这些蛋白质都受到高频率的大小变化，由于滑链错配，导致重复单位的增益或损失。这些重复蛋白质的功能和大小变化的表型后果是未知的。在鼠病原体肺支原体中，Vsa蛋白的大小变化调节支原体的生长特性（菌落大小变化）、红细胞吸附和对补体裂解的敏感性。我们的长期目标是了解支原体的致病机制。目前的建议的目标是研究的功能和致病意义的Vsa大小的变化。包括M.肺具有细胞外基质。我们认为这种基质是由Vsa蛋白组成的，用于保护支原体免受补体的侵害。目的1是通过电子显微镜检查基质，以确定它是否由Vsa蛋白组成，并确定它是否是补体的屏障。Vsa蛋白可能影响支原体和宿主细胞之间的相互作用，将在目的2中检查Vsa是否调节支原体对吞噬作用的敏感性。在目的3中，将通过比较产生大（许多串联重复）或小（很少重复）Vsa蛋白的细胞在免疫活性和补体缺陷小鼠中定殖和致病的能力来研究Vsa大小变化的致病意义。这些研究的结果将阐明高度重复的蛋白质在支原体疾病中的作用。他们还将深入了解其他微生物中对公共卫生至关重要的重复蛋白质的功能，包括负责疟疾，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。

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.