Characterizing IL-22 driven chronic immune activation in HIV/TB co-pandemic

HIV/TB 共流行中 IL-22 驱动的慢性免疫激活的特征

基本信息

批准号：
10553148
负责人：
Riti Sharan
金额：
$ 18.9万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553148
关键词：
Address Antibody Therapy Biological Markers Blood Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Separation Cells Chronic Colorectal Country Data Defensins Dendritic Cells Development Disease Disease Progression Epidemic Epithelial Cells Epithelium Frequencies Gene Expression Profiling Growth HIV HIV Infections HIV/TB Healthcare Human IL17 gene Immune response Immunity Immunomodulators Individual Infection Inflammation Interferon Type II Intervention Lung Lymphoid Tissue Macaca Macrophage Mediating Modeling Modernization Mononuclear Mucous Membrane Mycobacterium tuberculosis Natural regeneration Neutrophil Infiltration Pathologic Population Pre-Clinical Model Predisposition Production Proliferating Property Proteins Public Health Recombinants Regulation Resources Respiratory Disease Role S100A8 gene S100A9 gene SIV Signal Pathway Structure of parenchyma of lung T-Cell Depletion TNF gene Therapeutic Intervention Tissues Tuberculosis Viral Load result Work antimicrobial peptide antiretroviral therapy care burden co-infection cohort combinatorial cytokine driving force high risk immune activation insight interleukin-22 lung injury lymph nodes microbial mortality mycobacterial natural killer cell protein 44-kDa non-necrotizing granulomas nonhuman primate pandemic disease pathogen peripheral blood prevent reactivation from latency regenerative response targeted biomarker therapy development transmission process

项目摘要

Project Summary The Human Immunodeficiency Virus (HIV) and tuberculosis (TB) co-pandemic poses a major healthcare burden in resource-limited countries. HIV co-infection predisposes the host to reactivation of latent tuberculosis infection (LTBI) resulting in worsening of disease conditions and mortality. The most well characterized impact of HIV is the CD4+ T cell depletion in lymphoid tissues and peripheral blood. However, studies using the nonhuman primate (NHP) model of M. tuberculosis (Mtb)/SIV co-infection have revealed protective CD4+ T cell-independent immune responses that suppress LTBI reactivation. Recent work shows that the mere depletion of CD4+ T cells is insufficient to cause LTBI reactivation in SIV co-infected macaques. Instead, chronic immune activation appears to be the key correlate for reactivation. Further, highly effective combinatorial antiretroviral therapy (ART), while effective in reducing viral loads in the periphery and lungs of Mtb/SIV co-infected macaques, fails to reduce the rate of reactivation of LTBI. Thus, understanding the driving forces behind chronic immune activation in a relevant co-infected preclinical model underscores the discovery of key biomarkers and development of intervention strategies. We therefore aim to gain insight into the mechanism of mucosal damage, a paramount factor in chronic immune activation, during SIV/TB co-infection. Towards this end, we will investigate the role of IL-22, a key cytokine in protection from HIV and respiratory diseases including TB. We hypothesize that IL-22 protects the lung from damage during LTBI and SIV co-infection abrogates this protection by IL-22 perturbation. We aim to identify the mechanism by which IL-22 disarms the host immune response leading to SIV-driven immune activation and ultimately, the reactivation of LTBI, in a macaque model of SIV/TB co-infection. In Aim 1 we will study the functional role of IL-22 in Mtb/HIV co-infection. We will determine the levels of IL-22 production by CD4+ and CD8+ T cells as well as non-T-cell populations, NKp44+ cells, and CD103+ dendritic cells in the blood, lymph node and colorectum of co-infected macaques and in response to ART intervention (1a). We will also identify the frequency of polyfunctional Th17 cells producing IFNγ, IL-17, IL-22, TNFα, production of antimicrobial peptides; defensin-β, REG-3 proteins and S100A8/A9 proteins in the bronchoalveolar lavage fluid, colorectum, lung tissue lysates of co-infected macaques and in response to ART intervention (1b). In Aim 2, we will study the impact of SIV-induced IL-22 loss on LTBI reactivation. We will first determine whether the presence of IL- 22R expressing macrophages in non-necrotic granulomas of LTBI macaques correlates with protective control of Mtb (2a). We will then perform transcriptional profiling on sorted cell subsets and mononuclear cells isolated from blood, lymph nodes, lungs and colorectal mucosa before and after SIV infection to determine the impact of IL-22 loss on immune activation and subsequent LTBI reactivation (2b). Understanding the mechanism of IL-22 perturbation in HIV/TB will lead to identification and development of antibody-based therapeutics or use of recombinant IL-22 to prevent reactivation of LTBI in coinfected cohorts.

项目摘要人类免疫缺陷病毒（HIV）和结核病（TB）共同伴侣构成了主要的医疗保健伯恩在资源有限的国家。 HIV共感染使宿主重新激活潜在的结核病感染（LTBI）导致疾病状况和死亡率担心。艾滋病毒的影响最明显的是淋巴组织和外周血中的CD4+ T细胞耗竭。但是，使用非人类的研究结核分枝杆菌（MTB）/SIV共感染的灵长类动物（NHP）模型已显示受保护的CD4+ T细胞独立抑制LTBI重新激活的免疫反应。最近的工作表明，CD4+ T细胞的耗竭在SIV共感染的猕猴中引起LTBI重新激活不足。相反，慢性免疫激活似乎是重新激活的关键相关性。此外，高效的组合抗逆转录病毒疗法（ART），虽然有效减少MTB/SIV共感染的猕猴的外围和肺的病毒载荷失败降低LTBI重新激活的速率。那，了解慢性免疫背后的动力相关联的临床前模型中的激活强调了关键生物标志物的发现和开发干预策略。因此，我们旨在深入了解粘膜损伤的机制，这是慢性免疫的最高因素激活，在SIV/TB共感染期间。为此，我们将研究IL-22的作用，IL-22是关键的细胞因子免受包括结核病在内的艾滋病毒和呼吸系统疾病的保护。我们假设IL-22可保护肺部免受 LTBI和SIV共同感染期间的损害通过IL-22扰动消除了这种保护。我们旨在确定 IL-22解除宿主免疫响应的机制，导致SIV驱动的免疫激活和最终，在SIV/TB共感染的猕猴模型中，LTBI的重新激活。在AIM 1中，我们将研究 IL-22在MTB/HIV共感染中的功能作用。我们将通过CD4+和 CD8+ T细胞以及非T细胞种群，NKP44+细胞和血液中的CD103+树突状细胞，淋巴共同感染的猕猴的节点和结尾，并响应艺术干预（1A）。我们还将确定产生IFNγ，IL-17，IL-22，TNFα的多功能Th17细胞的频率，抗菌剂的产生肽；防御素-β，Reg-3蛋白和S100A8/A9蛋白在支气管肺泡灌洗液中，Colorectum，Colorectum，共同感染的猕猴的肺组织裂解物和对艺术干预的响应（1B）。在AIM 2中，我们将学习 SIV诱导的IL-22损失对LTBI重新激活的影响。我们将首先确定是否存在IL- 22R在LTBI猕猴的非新生肉芽肿中表达巨噬细胞与保护性控制 MTB（2a）。然后，我们将对分类的细胞集和分离的单核细胞进行转录分析从血液，淋巴结，肺和彩色粘膜中，SIV感染之前和之后，以确定 IL-22免疫激活和随后的LTBI重新激活的损失（2B）。了解IL-22的机制 HIV/TB中的扰动将导致基于抗体的治疗的鉴定和开发或使用重组IL-22以防止在共同感染的队列中LTBI重新激活。