Characteristics and protective efficacy of human antibodies against M. tuberculosis

摘要 活动性结核病（TB），一种由不受控制的分枝杆菌引起的可传播的呼吸道感染 结核病（Mtb）感染是全球十大死亡原因之一。为了控制这个主要的全球公众 健康问题迫切需要替代疗法和更有效疫苗。当前可用的 卡介苗（BCG）疫苗已经使用了几乎世纪，但提供的免疫应答不足。 预防TB。结核病疫苗领域的一个主要障碍是对结核病的全面认识有限， 免疫成分参与预防结核病。目前，结核病疫苗开发的重点是 在引发或增强细胞介导的免疫力，但越来越多的证据表明，抗体也有 在预防结核病方面的作用。为了更好地了解参与人类保护的表位， 和可诱导的疫苗接种，详细的表征和功能研究的人多克隆和 需要针对潜在保护性表位的单克隆抗体（mAb）。抗荚膜抗体和其他抗体 表面多糖对几种微生物病原体具有保护作用，包括那些具有细胞内 位置.使用新的聚糖阵列，我们发表的和初步的数据表明，人抗结核分枝杆菌表面 聚糖在其结合特异性方面是高度异质的，并且在其对寡糖的反应性方面是不同的。 BCG疫苗接种和/或控制（潜伏）与不控制（TB）Mtb之间的基序及其功能 感染我们的首要假设是：1）人抗AM抗体对Mtb具有保护作用，2）保护 通过这些Ab产生对AM内特定OS基序的反应性。我们的具体目标是：1.以生成和 表征针对Mtb表面聚糖的人多克隆抗体和mAb; 2.为了确定结核分枝杆菌表面的影响- 特异性人Ab对巨噬细胞功能的影响;和3.为了确定结核分枝杆菌表面的保护功效- 体内特异性人Ab。我们的首要目标是鉴定关键的免疫原性Mtb糖表位， Ab介导的人体保护作用。所获得的信息可以填补目前对以下问题的认识中的一个关键空白： 结核病免疫力，并为开发疫苗和基于Ab的免疫疗法提供新的战略 TB.

Abstract Active tuberculosis (TB), a transmissible respiratory infection caused by uncontrolled Mycobacterium tuberculosis (Mtb) infection, is worldwide one of the top 10 causes of death. To control this major global public health problem alternative therapies and a more effective vaccine are urgently needed. The currently available Bacillus Calmette-Guerin (BCG) vaccine has been in use for almost a century but provides insufficient protection against TB. A major obstacle in the TB vaccine field is the limited understanding of the full breadth of the immune components involved in the protection against TB. Currently, TB vaccine development is focused on eliciting or boosting cell-mediated immunity, but increasing evidence suggests that antibodies also have a role in the protection against TB. To gain a better understanding of the epitopes involved in human protection and inducible by vaccination, detailed characterization and functional studies of human polyclonal and monoclonal Abs (mAbs) to potentially protective epitopes are required. Antibodies to capsular and other surface polysaccharides are protective against several microbial pathogens, including those with intracellular location. Using novel glycan arrays our published and preliminary data show that human Abs to Mtb surface glycans are highly heterogeneous in their binding specificity and differ in both their reactivity to oligosaccharide motifs and their functions between BCG vaccination and/or controlled (latent) versus uncontrolled (TB) Mtb infection. Our overarching hypotheses are: 1) Human Abs to AM are protective against Mtb, and 2) protection by these Abs arises from reactivity to specific OS motifs within AM. Our specific aims are: 1. To generate and characterize human polyclonal and mAbs to Mtb surface glycans; 2. To determine the effects of Mtb surface- specific human Abs on macrophage functions; and 3. To establish the protective efficacy of Mtb surface- specific human Abs in vivo. Our overarching goal is to identify key immunogenic Mtb glycotopes that render Ab-mediated protection in humans. The information gained could fill a critical gap in the current knowledge of TB immunity and inform new strategies for developing both vaccines and Ab-based immunotherapies against TB.