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， 迫切需要感染。最近，有人提出分枝杆菌在调节 氧化还原应激可能是有效的疫苗候选者，因为这些可能会干扰几种 微生物抗氧化剂我们最近发现，应激反应因子SigH中的一个同基因Mtb突变体， 如果用于通过免疫途径免疫猕猴，则显著且令人印象深刻地保护免受同源Mtb感染。 气溶胶途径。 作为本申请的一部分，我们提出更好地理解粘膜保护性免疫的相关性。 使用一组不相互依赖的三个特定目标，用BissigH进行疫苗接种。此外，我们将研究 如果这种疫苗接种也可以保护免受Mtb的高感染性异源菌株（特异性 目标1）。在一系列的机制实验中，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 猕猴特异性试剂这些动物将同时接受高剂量同源Mtb攻毒 挑战，以评估在不存在B细胞的情况下是否去除了BissigH的保护功效（特异性目标2）。 最后，我们将研究诱导性支气管相关组织（iBALT）是否为SIV提供了一个避难所， 持续，或者iBALT是否保护Tfh细胞在共感染期间免于SIV的消耗（特异性目的3）。 作为这三个目标的一部分，所获得的结果将i）有可能建立一个 主要的活分枝杆菌抗TB疫苗载体; ii）在一个特定的抗TB疫苗载体中提供针对TB的保护的定义相关物， 模型系统，将提供直接适用于人体试验;和iii）定义有争议的作用 保护B细胞免受结核病的侵害。

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.