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

项目摘要 人类免疫缺陷病毒（HIV）和结核病（TB）的共同流行造成了重大的医疗负担 在资源有限的国家。艾滋病毒合并感染使宿主易于重新激活潜伏的结核病感染 （LTBI）导致疾病状况和死亡率恶化。艾滋病毒最明显的影响是 淋巴组织和外周血中的CD 4 + T细胞耗竭。然而，使用非人类 灵长类（NHP）模型;结核病（Mtb）/SIV共感染显示保护性CD 4 + T细胞非依赖性 抑制LTBI再激活的免疫反应。最近的研究表明，仅仅消耗CD 4 + T细胞， 不足以在SIV共感染的猕猴中引起LTBI再激活。相反，慢性免疫激活 似乎是重新激活的关键关联此外，高效的组合抗逆转录病毒疗法 (ART)虽然有效降低Mtb/SIV共感染猕猴外周和肺部的病毒载量， 以降低LTBI的再激活率。因此，了解慢性免疫缺陷背后的驱动力， 在相关的共感染临床前模型中的激活强调了关键生物标志物的发现， 制定干预战略。 因此，我们的目标是深入了解粘膜损伤的机制，粘膜损伤是慢性免疫性疾病中的一个重要因素。 在SIV/TB共感染期间激活。为此，我们将研究IL-22的作用，IL-22是一种关键的细胞因子， 保护免受艾滋病毒和呼吸道疾病，包括结核病。我们假设IL-22保护肺免受 在LTBI和SIV共感染期间的损伤通过IL-22干扰消除了这种保护。我们的目标是确定 IL-22解除宿主免疫应答的机制，导致SIV驱动的免疫激活， 最终，在SIV/TB共感染的猕猴模型中，LTBI的再激活。在目标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CD 4+和CD 4 + T细胞测定IL-22的产生水平。 血液、淋巴、淋巴结和淋巴结中的CD 8 + T细胞以及非T细胞群、NKp 44+细胞和CD 103+树突状细胞 结和结直肠的共感染猕猴和响应ART干预（1a）。我们还将确定 产生IFNγ、IL-17、IL-22、TNFα的多功能Th 17细胞的频率， 肽;支气管肺泡灌洗液，结肠直肠， 共感染猕猴的肺组织裂解物和对ART干预的响应（1b）。在目标2中，我们将研究 SIV诱导的IL-22损失对LTBI再激活的影响。我们将首先确定是否存在IL- LTBI猕猴非坏死性肉芽肿中表达22 R的巨噬细胞与保护性对照相关 Mtb（2a）。然后，我们将对分选的细胞亚群和分离的单核细胞进行转录谱分析 从血液、淋巴结、肺和结直肠粘膜中检测SIV感染前后的影响， 免疫活化和随后的LTBI再活化时的IL-22损失（2b）。了解IL-22的机制 艾滋病毒/结核病的干扰将导致识别和开发基于抗体的疗法或使用 重组IL-22以防止共感染队列中LTBI的再激活。

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.