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

摘要 结核病(TB)是世界范围内导致死亡的主要传染病，并导致相当大的发病率。 以及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 在怀孕/产后较高，但尚不清楚是否与怀孕相关的免疫学变化 导致了这种易感性的增加。提高了对影响M. 结核病(Mtb)感染和结核病严重程度是改善结核病治疗和疫苗所必需的。多重 一系列证据表明，怀孕会降低T细胞对病原体的免疫力，并可能损害先天免疫 对Mtb的认可。结核分枝杆菌感染后，巨噬细胞和树突状细胞启动免疫反应，导致 分枝杆菌杀灭、肉芽肿形成和T细胞激活。我们的长期目标是确定分子 以及影响结核病易感性的细胞机制。影响结核分枝杆菌的免疫变化的发现 孕期发病机制可能导致改善公共卫生努力，以减少结核杆菌的发病率和传播 在高危人群中。这项资助的目的是描述怀孕对先天和适应性的影响。 使用允许研究之前、期间和期间免疫反应的存储样本对结核分枝杆菌的免疫反应 怀孕后。核心假设是怀孕抑制了对结核分枝杆菌的先天性免疫反应。 有害的方式，削弱结核分枝杆菌特异性T细胞反应，增加结核病的易感性。其基本原理是 以一种微妙的方式识别影响结核分枝杆菌特异性先天免疫和T细胞免疫的因素提供了 一条通向合理疫苗设计的新途径，并提供了对高危人群的更好理解。我们的 特定的目标将检验以下假设：1)怀孕会降低CD_4+干扰素+T细胞的比例 潜在结核分枝杆菌感染孕妇的多功能TH1和CD8+T细胞；2)妊娠损害 外周血单核细胞诱生促炎细胞因子的能力增加 细胞内复制。这一贡献意义重大，因为它将建立起 在艾滋病毒方面受到怀孕的影响，使用来自怀孕前和怀孕后以及来自艾滋病毒的样本-- 未感染的妇女作为比较；这项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。建议的工作是创新的，因为我们组装了一个新的协作 在流行病学和免疫学方面拥有丰富经验的团队，以创新的方式分析银行样本 对照，在研究不足的人群(艾滋病毒感染者、孕妇)中，利用尖端统计工具， 测量先天免疫和T细胞反应。对怀孕作为一种免疫调节条件的洞察是 因为这种方法可能为新的疗法和疫苗提供新的靶点，并将提供 临床相关的流行病学和免疫学数据，为未来的结核病筛查和预防提供信息 儿童健康设置。

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.