Effects of HIV SIV on unconventional T cells in immunity to M. tuberculosis in pre adolescents

HIV SIV对青春期前结核分枝杆菌免疫中非常规T细胞的影响

基本信息

批准号：
10582697
负责人：
Lishomwa C Ndhlovu
金额：
$ 120.07万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2019-03-04 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582697
关键词：
Adolescent Adult Affect Animal Model Animals Antibodies Bacteria Biological Blood CD4 Positive T Lymphocytes Cell physiology Cells Child Childhood Chronic Clinic Clinical Clinical Data Cohort Studies Containment Cytotoxic T-Lymphocytes Data Defect Disease Event Frequencies Goals Granuloma HIV HIV Infections HIV-infected adolescents HIV/TB Harvest Health Humoral Immunities Immune Immune response Immune system Immunity Immunocompromised Host Impairment Infection Infection Control Lung Macaca Macaca fascicularis Measures Mediating Methods Modeling Mucous Membrane Myanmar Mycobacterium tuberculosis Outcome Pathologic Pediatric cohort Peripheral Peripheral Blood Mononuclear Cell Phenotype Population Predisposition Radiology Specialty Resistance Risk Risk Factors Role SIV Severities Specimen T-Lymphocyte Testing Tuberculosis Virus adaptive immune response adaptive immunity anti-PD-1 anti-PD1 antibodies antiretroviral therapy cell type co-infection cytokine exhaustion fighting functional improvement global health human disease immune function improved insight nonhuman primate novel pathogen pediatric human immunodeficiency virus preadolescence programmed cell death protein 1 recruit response tuberculosis granuloma

项目摘要

Project Summary Infection with Mycobacterium tuberculosis (Mtb) is a major global health problem in pediatric populations. Children coinfected with HIV and Mtb have an increased risk of developing tuberculosis (TB), even if they are on antiretroviral therapy. We know little about the specific immune defects caused by HIV that are responsible for the increased susceptibility to Mtb, especially in children. As an airborne pathogen, Mtb first encounters immune cells in the lung and the initial response to the infection can dictate whether the host controls the infection or whether the bacteria replicate and spread, causing TB disease. Unconventional T cells, including CD1d- restricted invariant Natural Killer (NK)T cells and Mucosal-Associated Invariant T (MAIT) cells, can detect and destroy Mtb-infected cells and can act before adaptive immunity evolves. HIV impairs both cell types. In our ongoing studies of HIV/Mtb coinfection, using adult macaques and SIV as an HIV surrogate, we found that animals with chronic SIV infection are more susceptible to Mtb and that this is associated with elevated expression of immune exhaustion markers (e.g. PD-1) on MAIT cells. This suggests that SIV-dependent exhaustion of MAIT cells, and perhaps other unconventional T cells, may lower the resistance to Mtb. Here we will use juvenile macaques to model HIV/Mtb coinfected children and determine whether a preexisting SIV infection impairs MAIT and NKT cells. SIV-infected animals will be coinfected with Mtb and TB progression will be quantitatively measured by several clinical, radiologic, and pathologic methods. We will correlate the exhaustion phenotypes of MAIT and NKT cells with the severity of TB, comparing outcomes in SIV-positive vs SIV-naïve juvenile macaques. To formally test whether SIV-dependent exhaustion of MAIT and NKT cells impairs TB resistance, we will treat SIV-infected juvenile macaques with anti-PD-1 to reverse immune exhaustion of MAIT and NKT cells. Following Mtb coinfection, we will compare cellular and humoral immune function as well as TB severity in animals treated with anti-PD-1 to those treated with control antibody. We will also leverage an existing pediatric HIV study in Yangon, Myanmar (R01MH108559) to characterize unconventional T cell populations in pre-adolescents with and without HIV infection and HIV/Mtb coinfection. We will use PBMC to determine the relationship between HIV and TB status with peripheral MAIT and NKT cell frequencies, immune exhaustion status, and cellular function. Together, these studies will provide novel insights into the roles of MAIT and NKT cells, as well as immune exhaustion, in HIV/Mtb coinfection of pre-adolescent children and may identify targets for host-directed therapies aimed at improving the health outcomes of children living with HIV.

项目概要结核分枝杆菌 (Mtb) 感染是儿科人群的一个主要全球健康问题。同时感染 HIV 和 Mtb 的儿童患结核病 (TB) 的风险会增加，即使他们是我们对艾滋病毒引起的特定免疫缺陷知之甚少。对于结核分枝杆菌的易感性增加，特别是在儿童中，结核分枝杆菌是一种空气传播的病原体。肺部的免疫细胞和对感染的最初反应可以决定宿主是否控制感染或者细菌是否复制和传播，导致非常规 T 细胞，包括 CD1d-。限制性不变自然杀伤 (NK) T 细胞和粘膜相关不变 T (MAIT) 细胞，可以检测和破坏 Mtb 感染的细胞，并且可以在 HIV 损害这两种细胞类型之前发挥作用。正在进行的 HIV/Mtb 双重感染研究，使用成年猕猴和 SIV 作为 HIV 替代物，我们发现患有慢性 SIV 感染的动物更容易感染 Mtb，这与 Mtb 升高有关。 MAIT 细胞上免疫耗竭标记物（例如 PD-1）的表达表明 SIV 依赖性。 MAIT 细胞以及其他非常规 T 细胞的耗竭可能会降低对 Mtb 的抵抗力。将使用幼年猕猴来模拟 HIV/Mtb 双重感染儿童，并确定是否存在先前存在的 SIV 感染会损害 MAIT 和 NKT 细胞，感染 SIV 的动物将同时感染 Mtb 和 TB 进展。我们将通过多种临床、放射学和病理学方法进行定量测量。 MAIT 和 NKT 细胞的耗竭表型与结核病严重程度的关系，比较 SIV 阳性与首次接触过 SIV 的幼年猕猴，正式测试 SIV 依赖性的 MAIT 和 NKT 细胞耗竭是否会损害。结核病耐药性，我们将用抗PD-1治疗感染SIV的幼年猕猴，以逆转其免疫衰竭 MAIT 和 NKT 细胞合并 Mtb 后，我们还将比较细胞和体液免疫功能。作为用抗 PD-1 治疗的动物与用对照抗体治疗的动物的结核病严重程度，我们还将利用一种方法。缅甸仰光现有的儿科 HIV 研究 (R01MH108559) 旨在表征非常规 T 细胞我们将使用 PBMC 来检测有或没有 HIV 感染和 HIV/Mtb 合并感染的青春期前人群。确定 HIV 和 TB 状态与外周 MAIT 和 NKT 细胞频率、免疫这些研究将为 MAIT 的作用提供新的见解。和 NKT 细胞，以及免疫衰竭，在青春期前儿童的 HIV/Mtb 合并感染中，可能会识别旨在改善艾滋病毒感染儿童健康结果的宿主导向疗法的目标。