PE and PPE Function

PE 和 PPE 功能

• 批准号: 7500066
• 负责人: SARAH FORTUNE
• 金额: $ 20万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500066
• 关键词: Accounting; Acetylation; Antigenic Diversity; Antigens; Biology; Cell Wall; Clinical; Data; Disease; Environment; Family; Foundations; Future; Genes; Genetic; Genome; Genus Mycobacterium; Goals; Growth; Immune response; Immunologics; Infection; Localized; Mediating; Mediation; Modeling; Mycobacterium tuberculosis; Numbers; Pathogenesis; Pathway interactions; Peptide Signal Sequences; Play; Positioning Attribute; Post-Translational Protein Processing; Principal Investigator; Process; Protein Acetylation; Protein Family; Protein Secretion; Proteins; Proteomics; Range; Reporter; Research; Role; Staging; Structure; Surface; System; Testing; Thinking; Tuberculosis; Virulence; Work; base; defined contribution; immunogenicity; killings; latent infection; macrophage; mouse model; mycobacterial; novel; pathogen; pathogenic bacteria; programs; protein function; protein structure; tool; trafficking

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis has a unique repertoire of virulence mechanisms and generates a diverse spectrum of clinical disease. M. tuberculosis has two large families of proteins, the PE and the PPE proteins, which are likely to be critical to virulence. The PE and PPE proteins are rare in nonpathogenic mycobacteria but account for four percent of the M. tuberculosis genome. Many are secreted or surface localized and thus perfectly positioned to play critical roles in host-pathogen interactions. It has been difficult to use genetics to define the function of these proteins because of the sheer number of potentially redundant gene products. However, the fact that PE and PPE proteins are secreted in the absence of a signal sequence for the general secretory pathway suggests that there is an alternative secretion system for these proteins. In Aim 1, we will identify and target this secretion pathway in M. tuberculosis. We expect that by disrupting the appropriate processing of some or all PE and PPE proteins, we will define the contribution of these proteins to the growth and virulence of M. tuberculosis. In the Aim 2, we will study the relationship between PE and PPE protein secretion, post-translational modification and the immunogenicity of these proteins. This work will refine our model of how PE and PPE proteins generate antigenic diversity in M. tuberculosis. Together, these data will dramatically increase our understanding of PE and PPE proteins and provide a foundation for future studies of their function and role in pathogenesis Despite the fact that tuberculosis kills millions of people annually, little is known about how it causes disease. Here we will develop tools to define the function of a unique family of mycobacterial proteins, the PE and PPE proteins that are likely to be critical to virulence. This work will provide a foundation for understanding the role of these proteins in the interaction between M. tuberculosis and the infected host.

描述（由申请人提供）：结核分枝杆菌具有独特的毒力机制，并产生多种临床疾病。结核分枝杆菌有两大蛋白质家族：PE 和 PPE 蛋白质，它们可能对毒力至关重要。 PE 和 PPE 蛋白在非致病性分枝杆菌中很少见，但占结核分枝杆菌基因组的 4%。许多是分泌的或表面定位的，因此完美地在宿主-病原体相互作用中发挥关键作用。由于潜在冗余基因产物的数量巨大，因此很难利用遗传学来定义这些蛋白质的功能。然而，PE 和 PPE 蛋白在一般分泌途径的信号序列不存在的情况下分泌的事实表明，这些蛋白存在替代的分泌系统。在目标 1 中，我们将识别并靶向结核分枝杆菌中的这一分泌途径。我们期望通过破坏部分或全部 PE 和 PPE 蛋白的适当加工，我们将确定这些蛋白对结核分枝杆菌生长和毒力的贡献。在目标2中，我们将研究PE和PPE蛋白分泌、翻译后修饰以及这些蛋白的免疫原性之间的关系。这项工作将完善我们的 PE 和 PPE 蛋白如何在结核分枝杆菌中产生抗原多样性的模型。总之，这些数据将极大地增加我们对 PE 和 PPE 蛋白的理解，并为未来研究它们的功能和在发病机制中的作用奠定基础。 尽管结核病每年夺去数百万人的生命，但人们对其致病机制却知之甚少。在这里，我们将开发工具来定义独特的分枝杆菌蛋白家族的功能，即可能对毒力至关重要的 PE 和 PPE 蛋白。这项工作将为了解这些蛋白质在结核分枝杆菌和感染宿主之间的相互作用中的作用奠定基础。