"Determinants of T Cell Immunity to Tuberculosis Vaccines"

有效的宿主对结核分枝杆菌的免疫依赖于T细胞介导的对结核杆菌抗原的反应。我们最近的工作表明，结核分枝杆菌在其基因组途径中编码，促进逃避或颠覆宿主免疫，并干扰活的、减毒的分枝杆菌菌株的有效疫苗接种。在以前的工作中，我们已经识别了多个免疫逃避基因，并证明了它们的失活或缺失可以导致更具免疫原性的、减毒的活分支杆菌疫苗。在这个项目中，我们将在这个背景下开发新的活的结核分枝杆菌菌株，在受感染的动物中产生增强的T细胞反应和更强大的保护性免疫。还将引入突变以消除毒力，即使在免疫缺陷的情况下也是如此，从而创造出原则上在人类人口中广泛使用的疫苗毒株。此外，我们将在活的分枝杆菌疫苗菌株中加入化学佐剂，以及几种增强二次反应的方法，以进一步加强疫苗对结核病的预防作用。提出了三个具体目标：1)评估结核分枝杆菌突变对T细胞反应的影响；2)鉴定和鉴定可增强MHC 11类抗原提呈的结核分枝杆菌突变体；3)将基因修饰与化学佐剂和增强策略相结合，以增强结核分枝杆菌减毒疫苗株诱导的T细胞应答和保护效力。这些研究的长期目标是确立一些原则，这些原则将导致更安全和更有效的结核分枝杆菌活疫苗，这将有助于控制全球结核病负担和减少多药耐药菌株的出现。该项目通过寻求提高结核分枝杆菌减毒活疫苗的免疫原性，并通过分析特定的细胞免疫反应来建立保护的相关性，与该项目的总体目标有关。建议与P01资助计划的其他组成部分进行广泛的互动，该项目将从P01支持的各种核心资源中受益匪浅。

Effective host immunity to Mycobacterium tuberculosis is dependent on T cell-mediated responses against antigens of the bacillus. Our recent work has shown that M.tuberculosis encodes In its genome pathways that promote evasion or subversion of host immunity, and that these interfere with effective vaccination by live, attenuated mycobacterial strains. In previous work, we have identified multiple immune evasion genes and have demonstrated that their inactivation or deletion can lead to more immunogenic, attenuated live mycobacterial vaccines. In this project, we will build on this background to develop novel live M. tuberculosis strains that generate enhanced T cell responses and more robust protective immunity in infected animals. Mutations will also be introduced to eliminate virulence even in the setting of immunodeficiency, thus creating vaccine strains that will in principle be safe for widespread use in human populations. In addition, we will use the incorporation of chemical adjuvant into live mycobacterial vaccine strains and several approaches to boosting of secondary responses to further enhance vaccine-induced protection against tuberculosis. Three specific aims are proposed: 1) Assess the impact of mutations In M. tuberculosis that enhance apoptosis of infected host cells on T cell responses; 2) Identify and characterize mutants of M. tuberculosis that enhance antigen presentation by MHC class 11; 3) Combine genetic modifications with chemical adjuvant and boosting strategies to enhance T cell response and protective efficacy induced by attenuated M. tuberculosis vaccine strains. The long term goal of these studies is to establish principles that will lead to safer and more effective live M. tuberculosis vaccines that will contribute to controlling the global burden of tuberculosis and to reducing the emergence of multidrug resistant strains. This project relates to the overall goals of this program project by seeking to improve the immunogenicity of live attenuated M. tuberculosis vaccines, and by establishing correlates of protection through the analysis of specific cellular immune responses. Extensive interactions with other components of the P01 funded program are proposed, and the project will benefit significantly from the various core resources supported by the P01.