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

项目概要 人类免疫缺陷病毒 (HIV) 和结核病 (TB) 共同流行造成了重大的医疗负担 在资源有限的国家。 HIV 合并感染使宿主易于重新激活潜伏性结核感染 （LTBI）导致疾病状况和死亡率恶化。 HIV 最明显的影响是 淋巴组织和外周血中的 CD4 T 细胞耗竭。然而，使用非人类的研究 结核分枝杆菌 (Mtb)/SIV 共感染的灵长类 (NHP) 模型揭示了不依赖于 CD4 T 细胞的保护性 抑制 LTBI 再激活的免疫反应。最近的研究表明，仅仅消除 CD4 T 细胞 不足以引起 SIV 共感染猕猴中 LTBI 的重新激活。相反，慢性免疫激活 似乎是重新激活的关键相关因素。此外，高效的联合抗逆转录病毒疗法 (ART) 虽然可以有效减少 Mtb/SIV 共同感染的猕猴外周和肺部的病毒载量，但失败了 降低 LTBI 的再激活率。因此，了解慢性免疫背后的驱动力 相关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的一个重要因素。 SIV/TB 合并感染期间的激活。为此，我们将研究 IL-22（一种关键细胞因子）在 预防艾滋病毒和呼吸道疾病，包括结核病。我们假设 IL-22 可以保护肺部免受 LTBI 和 SIV 共同感染期间的损伤会消除 IL-22 扰动的这种保护作用。我们的目标是确定 IL-22 解除宿主免疫反应并导致 SIV 驱动的免疫激活的机制 最终，在 SIV/TB 合并感染的猕猴模型中 LTBI 重新激活。在目标 1 中，我们将研究 IL-22 在 Mtb/HIV 共感染中的功能作用。我们将确定 CD4 和 IL-22 产生的水平 血液、淋巴液中的 CD8 T 细胞以及非 T 细胞群、NKp44 细胞和 CD103 树突状细胞 共同感染的猕猴的淋巴结和结肠直肠以及对 ART 干预的反应 (1a)。我们还将确定 多功能 Th17 细胞产生 IFNγ、IL-17、IL-22、TNFα 的频率，抗菌剂的产生 肽；支气管肺泡灌洗液、结直肠、 共同感染的猕猴的肺组织裂解物以及对 ART 干预的反应 (1b)。在目标 2 中，我们将学习 SIV 诱导的 IL-22 丢失对 LTBI 再激活的影响。我们首先确定是否存在IL- LTBI 猕猴非坏死肉芽肿中表达 22R 的巨噬细胞与保护性控制相关 山地车 (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分析 从SIV感染前后的血液、淋巴结、肺部和结直肠粘膜来确定SIV感染前后的影响 免疫激活和随后的 LTBI 重新激活时 IL-22 丢失 (2b)。了解 IL-22 的机制 HIV/TB 的扰动将导致基于抗体的疗法的识别和开发或使用 重组 IL-22 可防止共感染人群中 LTBI 的重新激活。

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.