Immune Correlates of Protection from TB

抽象的。由于结核病仍然是一种导致广泛死亡的感染，因此有效的结核分枝杆菌疫苗 正在紧急寻找感染者。最近，有人提出分枝杆菌在调节中减弱 氧化还原应激可能是有效的候选疫苗，因为它们可能会干扰几种物质的产生 微生物抗氧化剂。我们最近发现应激反应因子 SigH 中存在同基因 Mtb 突变体 如果用于通过 气溶胶路线。 作为本应用的一部分，我们建议更好地了解粘膜保护性免疫的相关性 接种 sigH，使用一组三个不相互依赖的具体目标。另外我们还会学习 此类疫苗接种是否也能预防高传染性异源结核分枝杆菌菌株的感染（具体 目标1）。在一系列机械实验中，我们将耗尽招募到肺 iBALT 滤泡的 B 细胞 使用最近开发和优化的方法接种 sigH 突变体疫苗后，大量 猕猴特异性试剂。这些动物将同时接受高剂量同源 Mtb 的攻击 评估在没有 B 细胞的情况下 sigH 的保护功效是否会被削弱的挑战（具体目标 2）。 最后，我们将研究诱导支气管相关组织 (iBALT) 是否为 SIV 提供庇护所 持续存在，或者 iBALT 是否可以保护 Tfh 细胞在共感染期间免受 SIV 消耗（具体目标 3）。 作为这三个目标的一部分所获得的结果将 i) 有可能将 sigH 确立为 领先的活分枝杆菌抗结核疫苗载体； ii) 提供预防结核病的定义相关性 可立即应用于人体试验的模型系统； iii) 定义有争议的角色 B 细胞在预防结核病方面的作用。

Abstract. Since TB remains an infection that results in extensive mortality, efficacious vaccines against Mtb infection are urgently sought. Recently, it has been proposed that mycobacteria attenuated in the regulation of redox-stress may be effective vaccine candidates, since these could interfere with the production of several microbial antioxidants. We have recently shown that an isogenic Mtb mutant in stress-response factor SigH significantly and impressively protects against homologous Mtb infection if used to immunize macaques via the aerosol route. As part of this application we propose to better understand correlates of protective immunity upon mucosal vaccination with sigH, using a set of three specific aims that are not inter-dependent. In addition we will study if such vaccination can also protect against infection with highly infectious heterologous strains of Mtb (Specific Aim 1). In a series of mechanistic experiments, we will deplete B-cells recruited to the lung iBALT follicles in great numbers following vaccination with the sigH mutant, using a recently developed and optimized macaque-specific reagent. These animals will be concurrently challenged with a high-dose homologous Mtb challenge to assess if the protective efficacy of sigH is eviscerated in the absence of B-cells (Specific Aim 2). Finally, we will study if inducible bronchus associated tissue (iBALT) provides a sanctuary where SIV can persist, or whether iBALT protects Tfh cells from depletion by SIV during co-infection (Specific Aim 3). Together the results obtained as part of these three aims will i) have the potential to establish sigH as a leading live-mycobacterium anti-TB vaccine vehicle; ii) provide defining correlates of protection from TB in a model system which would provide immediate applicability in human trials; and iii) define the controversial role of B-cells in protection from TB.