Role of IL-17 Cytokine Networks in TB Relapse Due to HIV

IL-17 细胞因子网络在 HIV 导致的结核病复发中的作用

基本信息

批准号：
10622499
负责人：
Evans I Amukoye
金额：
$ 60.18万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-21 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10622499
关键词：
Acceleration Acute Adherence Affect Animal Model Animals Automobile Driving Bacillus Biological CD4 Positive T Lymphocytes Cause of Death Cell Count Cells Cellular Immunity Cellular Structures Cessation of life Clinical Combination Drug Therapy Communicable Diseases Complement Complex Containment Cytokine Network Pathway Cytokine Signaling Data Defect Development Disease model Dose Experimental Models Family Flow Cytometry Functional disorder HIV HIV Infections HIV/TB High-Throughput RNA Sequencing Human IL17 gene Immune Immune System Diseases Immune response Immunity Impairment In Vitro Individual Interleukin-6 Intervention Investigation Kenya Knowledge Lung Mediating Memory Modeling Mycobacterium tuberculosis Outcome Pathway interactions Performance Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Pharmacotherapy Phase Play Population Predisposition Preventive measure Prospective Studies Public Health Recombinants Recovery Recurrence Relapse Research Risk Role Site Specimen System T-Lymphocyte Testing Treatment Failure Tuberculosis Viral Virus Virus Diseases Virus Replication chemotherapy co-infection cytokine detection limit drug resistance development gain of function human subject humanized mouse immune activation immune function in vivo interleukin-23 loss of function mouse model potential biomarker prognostic indicator response spectrograph therapy development transcription factor tuberculosis chemotherapy tuberculosis drugs tuberculosis treatment vaccination against tuberculosis

项目摘要

Abstract Tuberculosis (TB) claims the lives of 4,000 individuals every day as the leading cause of death due to infectious disease. In those with human immunodeficiency virus (HIV) infection, however, the risk for TB treatment failure or post-therapy relapse is greatly increased. TB relapse is strongly associated with development of drug resistance and occurs through poorly understood effects of HIV on host immunity. Understanding the HIV factors driving TB relapse, then, represents an important gap in knowledge needed for development of interventions that support immune containment and complement drug therapy. We describe the first animal model of HIV- mediated TB relapse following drug treatment, using the humanized mouse. Our preliminary data suggests that defects in activation of IL-17 pathways due to HIV infection are a potential mechanism for loss of immunity to the causative agent of TB, Mycobacterium tuberculosis (Mtb). Based on these findings, we hypothesize that Th17 T cells play an important role in containment of paucibacillary TB following drug therapy that is compromised by HIV infection. Our collaborative group previously conducted investigations of T cell immune defects in HIV+ and HIV- human subjects in Nairobi, Kenya, who had recently completed the intensive phase of TB chemotherapy. We propose to expand our investigations to now demonstrate how HIV status effects Th17 cell memory function following TB chemotherapy in virally suppressed and non-suppressed people. We propose to further use our humanized mouse model of HIV-mediated TB relapse to identify the mechanistic role of Th17 cells and IL-17 in TB containment, and demonstrate how activation of Th17 cells during the immune response to Mtb promotes virus propagation in the lung. We propose the following specific aims: 1) Aim 1, Poor recovery or dysfunction of the Th17 compartment predicts post-chemotherapy TB relapse in human subjects with HIV; and 2) Aim 2, HIV co-infection perturbs protective function of Th17/IL-17 as a mechanism for driving Mtb relapse following TB drug therapy in co-infected humanized mice. We expect these results to inform efforts to target the IL-17 cytokine family in development of preventive measures to reduce TB recurrence in those at risk due to HIV co-infection.

抽象的结核病（TB）每天夺取4,000个人的生命，是由于传染性而导致的死亡原因疾病。但是，在患有人类免疫缺陷病毒（HIV）感染的人中，结核病治疗失败的风险或治疗后复发大大增加。结核病复发与药物的发展密切相关抗药性和通过对艾滋病毒对宿主免疫的影响不足而发生。了解艾滋病毒因素因此，驱动结核病复发代表了开发干预所需的知识的重要差距支持免疫遏制并补充药物治疗。我们描述了艾滋病毒的第一个动物模型药物治疗后介导的结核病复发，使用人源化小鼠。我们的初步数据表明由于HIV感染引起的IL-17途径的激活缺陷是丧失免疫力的潜在机制结核病，结核分枝杆菌（MTB）的病因。基于这些发现，我们假设TH17 在药物疗法后，T细胞在遏制paucibibainlary TB的遏制中起着重要作用。艾滋病毒感染。我们的协作小组先前对HIV+和肯尼亚内罗毕的艾滋病毒受试者最近完成了TB化疗的密集阶段。我们建议将我们的调查扩展到现在证明HIV状态如何影响TH17细胞记忆功能在病毒抑制和不受抑制的人中进行结核病化疗之后。我们建议进一步使用我们的 HIV介导的TB复发的人源化小鼠模型，以鉴定Th17细胞和IL-17在 TB遏制，并证明在免疫反应中Th17细胞的激活如何促进肺中的病毒传播。我们提出以下具体目的：1）目标1，恢复不良或功能障碍 TH17室预测，艾滋病毒的人类受试者的化学后结核病复发。 2）AIM 2，艾滋病毒 TH17/IL-17的共同感染遗产保护功能作为驱动MTB复发的机制共同感染的人源性小鼠的治疗。我们希望这些结果能够为瞄准IL-17细胞因子的努力提供信息制定预防措施的家庭，以减少因艾滋病毒共同感染而有风险的人的结核病复发。