HIV-induced transcriptional changes in alveolar macrophages in susceptibility to M. tuberculosis infection

项目总结/摘要 人类免疫缺陷病毒（HIV）感染与24至28倍的活性增加有关。 肺结核（TB），肺泡巨噬细胞（AM）受HIV和分枝杆菌感染 结核病（Mtb）。在未经治疗和接受抗逆转录病毒（ART）治疗的患者中，AM对HIV储存库的贡献 艾滋病毒感染者的情况还不清楚，直接感染或旁观者AM对艾滋病毒感染的贡献也不清楚。 在HIV感染的肺中观察到的细胞功能障碍。艾滋病毒感染增加活动风险的机制 结核病感染也不清楚。我们的初步数据来自于对来自患有 未经治疗的HIV感染和健康对照表明，HIV诱导AM上调特定的 炎症基因，包括CCL 2，它招募单核细胞到组织中。我们观察到艾滋病毒相关的 AM中CCL 2转录物的上调和支气管肺泡灌洗（BAL）中CCL 2蛋白水平的增加 液CCL 2与人类、小鼠和斑马鱼对活动性结核病的易感性增加有关， HIV诱导的CCL 2产生与活动性结核病风险增加无关。我们建议研究BAL 来自HIV感染和未感染个体的样品，并使用体内模型系统以评估 直接和间接HIV感染对AM的频率和影响，以及HIV诱导AM的机制 CCL 2的产生及其在结核病易感性中的作用为了实现这一目标，我们将首先研究 HIV感染的AM，并测量不同类型的HIV感染和暴露对AM的影响。接下来我们 将研究HIV感染者肺部巨噬细胞募集的变化，并建立CCL 2诱导的模型。 在Mtb感染的小鼠中进行巨噬细胞募集，以了解这如何调节活动性TB的风险。的 这些目标的结果将使我们能够确定艾滋病毒对AM的影响，阐明一个关键机制， 驱动艾滋病毒相关结核病，并确定结核病的新型宿主导向治疗靶点。

Project Summary/Abstract Human immunodeficiency virus (HIV) infection is associated with a 24- to 28-fold increase in active tuberculosis (TB), with alveolar macrophages (AMs) subject to infection by both HIV and Mycobacterium tuberculosis (Mtb). The contribution of AMs to the HIV reservoir in untreated and antiretroviral (ART)-treated people with HIV is not well understood, nor is the contribution of directly infected or bystander AMs to the cellular dysfunction seen in HIV infected lungs. The mechanisms by which HIV infection increases risk of active TB infection are also unclear. Our preliminary data from transcriptional analysis of AMs from individuals with untreated HIV infection and healthy controls suggest that HIV induces AMs to upregulate specific sets of inflammatory genes, including CCL2, which recruits monocytes to tissues. We observed HIV-associated upregulation of CCL2 transcripts in AMs and increased CCL2 protein levels in bronchoalveolar lavage (BAL) fluid. CCL2 has been associated with increased susceptibility to active TB in humans, mice and zebrafish, but HIV-induced CCL2 production has not been linked to increased risk of active TB. We propose to study BAL samples from HIV-infected and -uninfected individuals and use in vivo model systems in order to assess the frequency and impact of direct and indirect HIV infection on AMs and the mechanisms behind HIV-induced CCL2 production and its role in susceptibility to TB. To accomplish this goal, we will first study the frequency of HIV-infected AMs and measure the effects of different types of HIV infection and exposure on AMs. Next, we will study changes in macrophage recruitment in the lungs of HIV-infected people and model CCL2-induced macrophage recruitment in Mtb-infected mice to understand how this may modulate the risk of active TB. The results of these aims will enable us to define the effects of HIV on AMs, elucidate a key mechanism that may drive HIV-associated TB, and identify novel host-directed therapeutic targets for TB.