Dynamics of tuberculosis immune response in peripartum HIV-infected and HIV-uninfected women

摘要 结核病（TB）是全世界死亡的主要传染性原因，并导致大量的发病率 感染艾滋病毒的围产期妇女及其子女的死亡率。活动性结核病的风险似乎是 怀孕期间/产后更高，但尚不清楚是否与怀孕相关的免疫学变化 增加了这种敏感性。提高了对影响M的宿主因素的理解。 结核病（Mtb）感染和结核病严重程度的研究，以改善结核病治疗和疫苗。多 一系列证据表明，怀孕减少了T细胞对病原体的免疫力，并可能损害先天免疫 Mtb的识别Mtb感染后，巨噬细胞和树突状细胞启动免疫应答，导致 分枝杆菌杀灭、肉芽肿形成和T细胞活化。我们的长期目标是确定 以及影响结核病易感性的细胞机制。发现影响结核分枝杆菌的免疫变化 妊娠期发病可能导致改善公共卫生工作，以减少结核病发病率和传播 在高危人群中。这项补助金的目的是描述怀孕对先天和适应性的影响， 使用储存的样品，允许研究免疫反应前，期间， 怀孕后核心假设是，怀孕会抑制结核病患者对结核分枝杆菌的先天免疫反应， 有害的方式，削弱结核特异性T细胞反应和增加结核病易感性。其基本原理是 以微妙的方式影响结核分枝杆菌特异性先天免疫和T细胞免疫的因素的鉴定提供了 这是一条通往合理疫苗设计的新途径，并提供了对高危人群的更好理解。我们 具体的目的是检验以下假设：1）妊娠减少了CD4 + IFN γ + T细胞的比例 和多功能的TH1和CD8 + T细胞在潜伏性结核分枝杆菌感染的孕妇;和2）妊娠损害 外周血单核细胞诱导Mtb的促炎细胞因子的能力，并允许增加 细胞内复制这一贡献是重要的，因为它将建立免疫机制， 在艾滋病毒感染的情况下，使用怀孕前和怀孕后以及艾滋病毒感染者的样本， 未受感染的妇女作为比较;这一建议将导致更好地了解怀孕的影响 巨噬细胞和T细胞生物学。拟议的工作是创新的，因为我们组建了一个新的协作团队 在流行病学和免疫学方面拥有丰富经验的团队， 控制，在研究不足的人群（艾滋病毒感染者，孕妇），利用先进的统计工具， 测量先天免疫和T细胞反应。了解怀孕作为一种免疫调节条件， 因为这种方法可以为新型疗法和疫苗提供新的靶点， 临床相关的流行病学和免疫学数据，为未来孕产妇结核病筛查和预防提供信息 儿童保健设施。

ABSTRACT Tuberculosis (TB) is the leading infectious cause of death worldwide, and contributes to substantial morbidity and mortality among HIV-infected peripartum women and their children. Risk of active TB appears to be higher during pregnancy/postpartum, but it is not known whether pregnancy-associated immunologic changes contribute to this increased susceptibility. Improved understanding of the host factors that influence M. tuberculosis (Mtb) infection and TB disease severity is needed to improve TB treatments and vaccines. Multiple lines of evidence indicate pregnancy diminishes T cell immunity to pathogens and may impair innate immune recognition of Mtb. After Mtb infection, macrophages and dendritic cells initiate the immune response, leading to mycobacterial killing, granuloma formation, and T cell activation. Our long-term goal is to determine the molecular and cellular mechanisms that influence susceptibility to TB. Discovery of the immune changes that influence Mtb pathogenesis in pregnancy may lead to improved public health efforts to reduce Mtb morbidity and transmission in at-risk populations. The objective of this grant is to characterize the effect of pregnancy on innate and adaptive immune responses to Mtb using stored samples that permit the study of immune responses pre-, during, and post-pregnancy. The central hypothesis is that pregnancy dampens the innate immune response to Mtb in a deleterious fashion, weakening Mtb-specific T cell responses and increasing TB susceptibility. The rationale is that identification of factors that influence Mtb-specific innate and T cell immunity in a nuanced fashion provides a novel path toward rational vaccine design and provides better understanding of high-risk populations. Our specific aims will test the following hypotheses: 1) pregnancy diminishes the proportion of CD4+IFN+ T cells and polyfunctional TH1 and CD8+T cells in pregnant women with latent Mtb infection; and 2) pregnancy impairs the capacity of peripheral blood monocytes to induce proinflammatory cytokines to Mtb and permits increased intracellular replication. This contribution is significant because it will establish the immune mechanisms that are influenced by pregnancy in the context of HIV, using samples from pre- and post-pregnancy and from HIV- uninfected women as a comparison; this proposal will lead to better understanding of the effects of pregnancy on macrophage and T cell biology. The proposed work is innovative because we assembled a new collaborative team with extensive experience in epidemiology and immunology to analyze banked samples with innovative controls, in an understudied population (HIV-infected, pregnant women), utilizing cutting-edge statistical tools, to measure innate immune and T cell responses. Insight into pregnancy as an immunomodulatory condition is impactful because this approach may offer new targets for novel therapeutics and vaccines, and will provide clinically relevant epidemiologic and immunologic data to inform future TB screening and prevention in maternal child health settings.