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)同时流行构成了主要的医疗负担 在资源有限的国家。HIV混合感染使宿主易于重新激活潜伏的结核病感染 (LTBI)导致病情恶化和死亡。艾滋病毒最典型的影响是 淋巴组织和外周血中CD4T细胞的耗竭。然而，使用非人类的研究 结核分枝杆菌(Mtb)/SIV混合感染的灵长类(NHP)模型揭示了保护性的CD4T细胞非依赖性 抑制LTBI重新激活的免疫反应。最近的研究表明，仅仅是CD4T细胞的枯竭 不足以在SIV混合感染的猕猴中引起LTBI的重新激活。相反，慢性免疫激活 似乎是重新激活的关键因素。此外，高效的联合抗逆转录病毒疗法 (ART)虽然在减少结核分枝杆菌/SIV混合感染猕猴外周和肺部的病毒载量方面有效，但失败了 以降低LTBI的复活率。因此，了解慢性免疫背后的驱动力 相关的联合感染临床前模型的激活强调了关键生物标记物和 制定干预策略。 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中的一个重要因素。 在SIV/TB混合感染期间激活。为此，我们将研究IL-22，一种关键的细胞因子在 预防艾滋病毒和包括结核病在内的呼吸道疾病。我们假设IL-22保护肺不受 在LTBI和SIV混合感染期间的损害取消了IL-22扰动的这种保护作用。我们的目标是确定 IL-22解除宿主免疫反应导致SIV驱动的免疫激活和 最终，在SIV/TB混合感染的猕猴模型中，LTBI重新激活。在目标1中，我们将研究 IL-22在结核分枝杆菌/HIV混合感染中的作用我们将测定CD_4和CD_4产生IL-22的水平 血液、淋巴中CD8 T细胞以及非T细胞群、NKp44细胞和CD103树突状细胞 混合感染猕猴的结节和结直肠以及对ART干预的反应(1a)。我们还将确定 多功能Th17细胞产生干扰素γ、IL-17、IL-22、肿瘤坏死因子α的频率、抗菌药物的产生 多肽；防御素-β、REG-3蛋白和S100A8/A9蛋白在支气管肺泡灌洗液、结肠、 混合感染猕猴的肺组织裂解物以及对ART干预的反应(1b)。在目标2中，我们将研究 SIV诱导的IL-22缺失对下丘脑损伤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22R的巨噬细胞与保护性对照相关 结核分枝杆菌(2a)。然后，我们将对分离的细胞亚群和单个核细胞进行转录图谱分析 从血液、淋巴、肺和大肠粘膜确定SIV感染前后的影响 IL-22在免疫激活和随后的LTBI重新激活方面的损失(2b)。对IL-22作用机制的认识 艾滋病毒/结核病的扰动将导致识别和开发基于抗体的疗法或使用 重组IL-22可防止LTBI在共感染队列中重新激活。

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.