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

HIV诱导的肺泡巨噬细胞转录变化对结核分枝杆菌感染的易感性

• 批准号: 9203596
• 负责人: Abigail Esther Schiff
• 金额: $ 3.43万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203596
• 关键词: Affect; Alveolar Macrophages; Anti-Retroviral Agents; Behavior; Biological Assay; Biological Models; Blood Circulation; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bystander Effect; CCL2 gene; Cells; Cellular Immunology; Data; Disease; Environment; Event; Family; Frequencies; Functional disorder; Future; Genes; Goals; Growth; HIV; Human; Immune; Immunologics; In Vitro; Individual; Infection; Infiltration; Inflammatory; Lead; Link; Lung; Measures; Mediating; Modeling; Mus; Mycobacterium tuberculosis; Pathogenesis; Peripheral; Predisposition; Production; Proteins; RNA; Recruitment Activity; Research; Risk; Role; Sampling; Severity of illness; System; Techniques; Technology; Tissues; Transcript; Tuberculosis; Up-Regulation; Viral reservoir; Virus Diseases; Work; Zebrafish; abstracting; base; beta-Chemokines; career; co-infection; cohort; human subject; in vivo; in vivo Model; insight; macrophage; monocyte; mouse model; novel; overexpression; prevent; skills; therapeutic target; transcriptome sequencing; viral DNA

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.

项目摘要/摘要 人类免疫缺陷病毒（HIV）感染与活性增加了24至28倍 结核病（TB），肺泡巨噬细胞（AMS）受HIV和分枝杆菌感染。 结核病（MTB）。 AMS对未治疗和抗逆转录病毒（ART）治疗的HIV储藏室的贡献 艾滋病毒患者不太了解，也不是直接感染或旁观者对 在HIV感染的肺中可见的细胞功能障碍。艾滋病毒感染增加活性风险的机制 结核病感染也不清楚。我们的初步数据来自来自患有AM的转录分析 未经治疗 炎症基因，包括CCL2，将单核细胞募集到组织。我们观察到与HIV相关 AMS中CCL2转录本的上调和支气管肺泡灌洗中CCL2蛋白水平升高（BAL） 体液。 CCL2与人类，小鼠和斑马鱼中对活性结核的敏感性增加有关，但是 HIV诱导的CCL2产生与活动性结核病风险的增加没有联系。我们建议研究BAL 来自HIV感染和未感染的个体的样本，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引起的机制 CCL2产生及其在TB易感性中的作用。为了实现这一目标，我们将首先研究 感染HIV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 将研究巨噬细胞募集的变化，在感染HIV的人的肺中，并模型CCL2诱导 MTB感染的小鼠中的巨噬细胞募集，以了解这可能如何调节活性结核病的风险。这 这些目标的结果将使我们能够定义艾滋病毒对AMS的影响，阐明一种可能的关键机制 驱动与HIV相关的结核病，并确定新型宿主定向的结核病靶标。