Tuberculosis and T cell Recognition

结核病和 T 细胞识别

基本信息

批准号：
9221970
负责人：
SAMUEL M BEHAR
金额：
$ 69.83万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9221970
关键词：
Adjuvant Affect Animal Model Anti-Bacterial Agents Antigen Presentation Antigens Attenuated Bacteria Bacterial Proteins Binding Proteins Biological Cells Cellular Immunity Defect Disease Engineering Epitopes Equilibrium Failure Goals Growth HIV Infections Heterogeneity Human Immune Immune response Immunity Impairment Infection Lead Lung Mediating Modeling Mus Mutate Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Myeloid Cells Organism Pattern Peptides Population Problem Solving Process Production Proteins Pulmonary Tuberculosis Regulation Research Research Proposals Signal Transduction Sterilization Subunit Vaccines T cell response T-Lymphocyte Testing Tuberculosis Vaccinated Vaccines Variant Virulent Work adaptive immunity antigen processing cell type design functional plasticity global health immune clearance improved killings macrophage multidisciplinary mycobacterial novel vaccines pathogen pressure protein degradation protein expression public health relevance success targeted treatment tool tuberculosis immunity vaccine development

项目摘要

DESCRIPTION (provided by applicant): Following virulent Mycobacterium tuberculosis (Mtb) infection in mice, a robust T cell response is primed in the draining LN, undergoes massive expansion, and traffics to the lung. Upon reaching the lung, T cells abort exponential bacterial growth, which leads to an early decline in bacterial burden followed by stabilization of the bacterial numbers long term. Despite T cell mediated clearance of most bacteria, sterilization is never achieved. Under optimal conditions, the best vaccines provide a 20-30-fold reduction in lung CFU. Thus, an optimal T cell response clears many but not all of the infecting bacteria-suggesting an important hurdle to achieving better protective immunity to infection is to determine why a relatively small, but biologically important subpopulation of bacteria survive in the face of otherwise effective T cell mediated immunity. Importantly, while the quantitative balance between successful immunity and failure may vary between animal models and people, both have features of both immune control and escape. Mice clear most bacteria after the onset of adaptive immunity but are unable to sterilize the lung, even if vaccinated. Thus, murine TB may be a reasonable model to explore why T cell immunity fails. Why might a subpopulation of bacteria survive in the face of a T cell response that can clear most of the bacterial population? There appears to be something different about the infectious course of the bacteria that survive in the face of robust adaptive immunity as compared to the ones that are cleared. Heterogeneity may arise at the level of the bacterium, the cellular compartment in which it resides, or the T cells that encounter infected cells. Understanding the balanced success and failure of T cell immunity to Mtb is important for determining how to better design a vaccine against Mtb infection. It is currently not clear whether making a new subunit vaccine with a different combination of antigens; application of a new adjuvant or a different attenuated strain of Mtb will solve this problem. We postulate that the first step towards designing a vaccine that elicits immunity that is better than that elicited by natural infection or current vaccines is identifying he features that drive immune failure. Our coordinated effort will investigate three fundamental questions about T cell immunity to Mtb, with the goal of having a major impact on vaccine development. Our overarching hypothesis is that bacteria survive despite a robust T cell response because of a local failure in T cell surveillance and effector function. Aim 1. Is T cell recognition of a subpopulation of infected cells impaired? We hypothesize that T cells recognize many but not all infected cells, and promote Mtb clearance. What remains is a population of infected cells that cannot be recognized or activated by T cells, and provides a niche for Mtb persistence. We will identify and determine why this niche emerges. Aim 2. Do quantitative differences in the bacterial population allow some Mtb cells to escape T cell clearance? We hypothesize that some infected cells escape recognition because expression of the early antigens that primed the immune response are downregulated later in infection. We will use bacterial strains that have been engineered to allow rheostat-like control of antigen production to determine whether quantitative differences in antigen load alter T cell recognition or effector function. Aim 3. Do distinct cell types process and present Mtb antigens differently? The T cell response reflects the antigens processed and presented by the priming DC. However, during HIV infection, intracellular processing of proteins and thus antigen presentation varies in different cell types (macrophages vs. DC) and with different activation states. We will test this hypothesis for Mtb infection, postulating that differences in the peptide epitopes presented by different cell types allow some infected cells to escape T cell surveillance.

描述（由申请人提供）：小鼠受到剧毒结核分枝杆菌 (Mtb) 感染后，引流淋巴结中会引发强烈的 T 细胞反应，经历大规模扩张，并在到达肺部后运输至肺部，T 细胞会中止呈指数增长的细菌。生长，导致细菌负荷早期下降，随后细菌数量长期稳定，尽管 T 细胞介导清除大多数细菌，但从未达到最佳灭菌效果。在这种情况下，最好的疫苗可以使肺部 CFU 减少 20-30 倍，因此，最佳的 T 细胞反应可以清除许多但不是全部的感染细菌，这表明实现更好的感染保护性免疫的一个重要障碍是确定为什么会产生感染。相对较小但具有生物学意义的细菌亚群在其他有效的 T 细胞介导的免疫面前得以生存。重要的是，虽然成功免疫和失败之间的定量平衡在动物模型和人类之间可能有所不同，但两者都具有免疫控制和逃避的特征。小鼠清除大多数细菌在获得适应性免疫后无法对肺部进行消毒，即使是肺炎，因此，小鼠结核病可能是探索为什么 T 细胞免疫失败的合理模型。能够清除大多数细菌群体的细胞反应？与被清除的细菌相比，在强大的适应性免疫中生存的细菌的感染过程似乎有所不同。异质性可能出现。细菌、细胞了解 T 细胞对 Mtb 免疫的成功和失败对于确定如何更好地设计针对 Mtb 感染的疫苗非常重要，目前尚不清楚是否要制作新的疫苗。具有不同抗原组合的亚单位疫苗；应用新佐剂或不同的 Mtb 减毒株；我们假设，设计一种能产生比自然感染或现有疫苗更好的免疫力的疫苗的第一步是确定导致免疫失败的特征，我们将共同努力研究有关 T 细胞免疫的三个基本问题。我们的总体假设是，尽管 T 细胞反应强劲，但由于 T 细胞监视和效应功能的局部失败，细菌仍能存活。目标 1。受感染细胞亚群我们目睹了 T 细胞识别许多但不是所有感染细胞，并促进 Mtb 清除，剩下的是 T 细胞无法识别或激活的感染细胞群，并为 Mtb 持久性提供了一个利基。目标 2. 细菌群体的数量差异是否会导致某些 Mtb 细胞逃避 T 细胞清除？我们将使用细菌菌株。目的 3. 不同的细胞类型对 Mtb 抗原的处理和呈递是否有所不同？然而，在 HIV 感染期间，不同细胞类型（巨噬细胞与 DC）的细胞内蛋白质加工和抗原呈递有所不同，并且具有不同的激活状态，我们将假设 Mtb 感染检验这一假设。不同细胞类型呈现的肽表位的差异使得一些受感染的细胞能够逃避 T 细胞的监视。