Modulation of Host Responses by Mycobacterium tuberculosis

 描述(申请人提供)：抗击结核病(TB)的战略，包括新的疗法和疫苗，取决于对结核分枝杆菌(Mtb)逃避宿主防御和调节免疫反应以使其受益的机制的更好理解。结核病领域的一个主要知识空白是我们缺乏对结核杆菌特异性T细胞反应为什么对结核病的保护作用不佳以及我们如何改善这些反应的洞察力。虽然干扰素-γ和辅助性T细胞1(Th1)对于控制结核分枝杆菌感染是必要的，但它们不足以预防结核病。最近，Th17细胞已成为结核病保护性免疫的重要细胞，但导致Th17亚群产生的机制尚不清楚。树突状细胞(DCs)通过细胞因子的产生、共刺激功能和抗原提呈对激活和形成抗原特异性T细胞分化至关重要，但Mtb调控DC功能和Th亚群形态分化的分子机制尚不清楚。本应用的重点是研究结核分枝杆菌调节DC功能的机制，研究结核分枝杆菌-DC相互作用如何影响结核分枝杆菌特异性Th1和Th17细胞免疫的产生，并利用这些见解设计更有效的结核病疫苗。我们建立在研究Mtb丝氨酸蛋白酶Hip1的分子和生化功能的基础上。我们发现了Hip1介导的一种新的免疫逃避机制，该机制通过靶底物GroEL2的蛋白分解来抑制TLR2依赖的先天反应，并削弱DC依赖CD40的共刺激能力。我们假设，Hip1介导的DC免疫调节促进次优抗原特异性T细胞反应，阻碍Mtb特异性Th17反应的产生，从而损害对结核病的保护性免疫。我们将结合分枝杆菌遗传学、免疫学和小鼠模型来研究GroEL2调控TLR2通路的分子基础、Th17反应及其在体内促进发病的作用(目标1)。其次，我们将研究CD40依赖的共刺激如何在结核病中形成DC-T细胞串扰，并测试增强CD40参与将增强Th17反应和保护性免疫的假设(目标2)。最后，我们将验证这样一种假设，即在卡介苗中删除HIP1将提高卡介苗在小鼠身上的效力(目标3)。这些研究将为结核分枝杆菌如何调节天然适应性免疫轴提供重要的见解，并为设计有效的结核病疫苗提供信息。

 DESCRIPTION (provided by applicant): Strategies for combating tuberculosis (TB), including new therapeutics and vaccines, depend on a better understanding of the mechanisms by which Mycobacterium tuberculosis (Mtb) evades host defenses and modulates immune responses to its benefit. A major knowledge gap in the TB field is our lack of insights into why Mtb-specific T cell responses are poorly protective against TB and how we can improve these responses. While IFN-γ and T-helper 1 (Th1) cells are necessary for controlling Mtb infection, they are not sufficient for protection against TB disease. Recently, Th17 cells have emerged as important for protective immunity to TB, but the mechanisms that lead to the generation of Th17 subsets remain unclear. Dendritic cells (DCs) are crucial for activating and shaping antigen-specific T cell differentiation through cytokine production, costimulatory functions and antigen presentation but the molecular mechanisms used by Mtb to manipulate DC functions and shape differentiation of Th subsets are poorly understood. The focus of this application is to investigat mechanisms used by Mtb to modulate DC functions, to examine how Mtb-DC interactions impact generation of Mtb-specific Th1 and Th17 cell immunity and to use these insights to design more efficacious TB vaccines. We build on insights gained from studying the molecular and biochemical functions of an Mtb serine protease, Hip1. We identified a novel immune evasion mechanism mediated by Hip1 that dampens TLR2- dependent innate responses through proteolysis of a target substrate, GroEL2 and impairs CD40-dependent costimulatory capacity of DCs. We hypothesize that Hip1-mediated immunomodulation of DCs promotes sub- optimal antigen-specific T cell responses, impedes generation of Mtb-specific Th17 responses and thereby compromises protective immunity to TB. We will combine mycobacterial genetics, immunology and mouse models to investigate the molecular basis for GroEL2 modulation of TLR2 pathways, Th17 responses and its role in promoting pathogenesis in vivo (Aim 1). Second, we will investigate how CD40-dependent costimulation shapes DC-T cell crosstalk in TB and test the hypothesis that boosting CD40 engagement will augment Th17 responses and protective immunity (Aim 2). Finally, we will test the hypothesis that deleting hip1 in BCG will improve efficacy of the BCG vaccine in mice (Aim 3). These studies will provide crucial insights into the how Mtb modulates the innate-adaptive immune axis and inform designing efficacious vaccines for TB.