Molecular mechanism of T cell evasion by Mycobacterium tuberculosis

 描述(申请人提供)：世界上约三分之一的人口感染结核分枝杆菌，世界卫生组织估计，2012年新增病例860万例，死亡100多万例。结核分枝杆菌能够通过颠覆宿主的固有和适应性防御来建立这种巨大的全球疾病负担。它做到这一点的一种方式是通过损害巨噬细胞和树突状细胞(DC)的关键细胞功能，破坏细菌的降解和向T细胞递送抗原。抗原提呈对于初始T细胞的启动和效应性T细胞识别感染的巨噬细胞都是至关重要的。因此，通过抑制抗原提呈，结核分枝杆菌阻止了有效的清除，并促进了持续感染。尽管它在结核分枝杆菌的发病机制和疫苗开发中具有明显的重要性，但我们对结核分枝杆菌如何抑制抗原提呈缺乏全面的了解。我们的研究小组最近发现，为了促进Mtb在细胞内的存活，Mtb会分泌EsxH，从而抑制运输所需的内体分选复合体(ESCRT)，ESCRT是宿主参与蛋白质运输的细胞机械。我们推测，通过靶向ESCRT，EsxH也会损害MHC-II抗原提呈。与这一想法一致，我的初步数据表明，结核分枝杆菌感染的巨噬细胞需要ESCRT来激活效应CD4+T细胞。相应地，感染缺乏EsxH的Mtb株的巨噬细胞比感染野生型Mtb的巨噬细胞更能激活CD4+T细胞，而过表达EsxH会削弱T细胞的激活。在本申请中，我试图扩展这些初步研究。我的目标是：1)确定EsxH和ESCRT调节巨噬细胞和DC的抗原提呈的机制；2)确定它们在体内对T细胞逃避的贡献。这些研究将大大增强我们对结核分枝杆菌逃避免疫反应的机制的理解。我们的发现可能为结核分枝杆菌感染过程中出现的适应性免疫反应启动延迟提供了解释。此外，我们的研究可能为结核分枝杆菌如何阻止效应CD4+T细胞直接识别感染细胞提供分子解释。因此，针对这种宿主-病原体的相互作用可能通过恢复巨噬细胞功能和T细胞激活来促进宿主对结核分枝杆菌的清除。

 DESCRIPTION (provided by applicant): Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and the World Health Organization estimates that in 2012 there were 8.6 million new cases and more than one million deaths. Mtb is able to establish this enormous worldwide burden of disease by subverting innate and adaptive defenses of the host. One way in which it does this is by impairing key cellular functions of macrophages and dendritic cells (DCs), undermining degradation of the bacilli and presentation of antigens to T cells. Antigen presentation is critical both for priming naïve T cells and for recognition of infected macrophages by effector T cells. Thus, by inhibiting antigen presentation, Mtb prevents effective clearance and promotes persistent infection. Despite its clear importance in Mtb pathogenesis and implications for vaccine development, we lack a comprehensive understanding of how Mtb inhibits antigen presentation. Our group recently found that to promote its intracellular survival, Mtb secretes EsxH, which inhibits the endosomal sorting complex required for transport (ESCRT), a cellular machinery of the host involved in protein trafficking. We hypothesize that by targeting ESCRT, EsxH also impairs MHC-II antigen presentation. Consistent with this idea, my preliminary data demonstrates that ESCRT is required for Mtb-infected macrophages to activate effector CD4+ T cells. Correspondingly, macrophages infected with an Mtb strain lacking EsxH elicited better activation of CD4+ T cells than macrophages infected with wild type Mtb, whereas overexpression of EsxH impairs T cell activation. In this application, I seek to extend these preliminary studies. My aims are to: 1) to define the mechanism by which EsxH and ESCRT modulate antigen presentation in both macrophages and DCs, and 2) to determine their contribution to T cell evasion in vivo. These studies will significantly augment our understanding of the mechanisms employed by Mtb to evade the immune response. Our findings may provide an explanation for the delay in the initiation of an adaptive immune response seen during Mtb infection. In addition, our studies may provide a molecular explanation for how Mtb prevents effector CD4+ T cells from directly recognizing infected cells. Thus, targeting this host-pathogen interaction might promote host clearance of Mtb by restoring macrophage function and T cell activation.