PE and PPE Function

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家族的蛋白，PE和PPE蛋白，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，因此完美地定位在宿主-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绝对数量，使用遗传学来定义这些蛋白质的功能一直很困难。然而，PE和PPE蛋白在缺乏一般分泌途径信号序列的情况下分泌，这一事实表明这些蛋白存在另一种分泌系统。在Aim 1中，我们将在结核分枝杆菌中识别和靶向这种分泌途径。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Aim 2中，我们将研究PE和PPE蛋白分泌、翻译后修饰和这些蛋白的免疫原性之间的关系。这项工作将完善我们关于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发病机制提供基础

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.