Characteristics and protective efficacy of human antibodies against M. tuberculosis

摘要 活动性肺结核(TB)，一种由不受控制的分枝杆菌引起的传染性呼吸道感染 结核病(Mtb)感染是世界范围内十大死亡原因之一。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的疫苗。当前可用的 卡介苗(BCG)已经使用了近一个世纪，但提供的疫苗还不够 预防结核病。结核病疫苗领域的一个主要障碍是对结核病疫苗的全面了解有限 参与预防结核病的免疫成分。目前，结核病疫苗的开发是重点。 关于激发或增强细胞免疫，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。为了更好地了解人类保护所涉及的表位 并可通过接种疫苗、详细鉴定和人类多克隆和功能研究而诱导 需要针对潜在保护性表位的单抗。抗囊膜抗体和其他 表面多糖对几种微生物病原体有保护作用，包括细胞内的病原体。 地点。利用我们发表的和初步的数据显示，利用新型的多聚糖阵列，人的抗体到结核分枝杆菌表面 多聚糖具有高度的异质性，它们与低聚糖的反应能力不同。 卡介苗接种和/或控制(潜伏)与非控制(TB)结核分枝杆菌之间的基序及其功能 感染。我们的主要假设是：1)人类抗AM抗体对结核分枝杆菌有保护作用，2)保护作用 通过这些抗体，AM中的特定操作系统模体会发生反应我们的具体目标是：1.产生和 鉴定人多克隆抗体和单抗对结核分枝杆菌表面糖链的影响；2.确定结核分枝杆菌表面糖链的作用 人特异性抗体对巨噬细胞功能的影响；以及3.确定结核分枝杆菌表面抗体的保护作用。 体内特异的人抗体。我们的首要目标是确定关键的免疫原性结核分枝杆菌糖蛋白 AB介导的人体保护。所获得的信息可能会填补目前对 结核病免疫和为开发疫苗和基于抗体的免疫疗法提供新的战略 结核病。

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.