Defining the antibody interface between Mycobacterium tuberculosis and host immunity

项目摘要/摘要： 结核病每年导致150万人死亡。减少这一数字的努力因缺乏而受到阻碍 有效的诊断和保护性疫苗的基础是对免疫反应的理解存在差距 在结核病方面。虽然细胞免疫很重要，但对分枝杆菌感染的体液免疫反应 结核病(结核分枝杆菌)知之甚少。抗体，特别是免疫球蛋白，是适应性免疫的关键成分。 在我们对传染病和疫苗的理解中不可或缺的免疫反应 发展。抗体的功能是通过结合Fab结构域识别抗原和 通过Fc结构域募集免疫效应反应。FC域中按同种类型、亚类、 翻译后糖基化影响免疫细胞与Fc受体的接触，改变免疫细胞的功能 临床上有意义的举止。我们已经发表了抗体Fc结构域在患有 与活动性结核病相比，看起来健康并能够限制细菌的潜伏感染 允许结核分枝杆菌复制。这些差异与体外原发人类中不同的结核分枝杆菌负荷有关。 单核细胞来源的巨噬细胞感染模型。抗体在这种情况下究竟如何发挥作用，以及它的 生理相关性是这项提案开始解决的问题。具体目标有一：确定 结核分枝杆菌抗原谱如何影响多克隆免疫球蛋白的功能，2：确定巨噬细胞通过什么途径 免疫球蛋白Fc对结核分枝杆菌存活的调节作用，3.检测多克隆抗体对慢性结核分枝杆菌感染的体内效应。这个 这项建议的科学目标是确定多克隆免疫球蛋白如何有助于限制性和允许性 Mtb的宿主国家。中心假设是来自活动性结核病患者的多克隆免疫球蛋白诱导 允许细菌生长的寄主国家。总体目标是了解 通过抗体实现结核病的体液免疫，为诊断、治疗和疫苗设计提供信息。

Project Summary/Abstract: Tuberculosis (TB) kills 1.5 million people per year. Efforts to reduce this number have been hindered by the lack effective diagnostics and a protective vaccine underpinned by gaps in the understanding of the immune response in TB disease. While cellular immunity is important, the humoral immune response to infection by Mycobacterium tuberculosis (Mtb) is poorly understood. Antibodies, specifically IgG, are critical components of the adaptive immune response which have been indispensable in our understanding of infectious diseases and vaccine development. Antibodies function through the combination of recognizing antigens by the Fab domain and the recruitment of immune effector responses via the Fc domain. Variability in the Fc domain by isotype, subclass, and post translational glycosylation impact engagement with Fc receptors on immune cells that alter function in clinically significant manners. We have published that the antibody Fc domain diverges between individuals with latent infection who appear healthy and able to restrict bacteria compared to active TB disease which is permissive to Mtb replication. These distinctions are linked to differential Mtb burden in an in vitro primary human monocyte derived macrophage model of infection. How exactly antibodies might function in this context and its physiological relevance are questions that this proposal begins to address. The specific aims are 1: Determine how the Mtb antigenic repertoire impacts polyclonal IgG functions, 2: Identify the macrophage pathways by which the IgG Fc modulates Mtb survival, 3: Examine the in vivo effect of polyclonal IgG on chronic Mtb infection. The scientific objective of this proposal is to determine how polyclonal IgG contributes to restrictive and permissive host states for Mtb. The central hypothesis is that polyclonal IgG from individuals with active TB disease induces a host state permissive to bacterial growth. The overall goal is to understand fundamental mechanisms of humoral immunity in TB through antibodies to inform diagnostic, therapeutic and vaccine design.