Single cell trancriptomics to identify LTBI reactivation markers in TB/HIV co-infection

单细胞转录组学鉴定结核病/艾滋病毒合并感染中的 LTBI 再激活标记

基本信息

批准号：
10685926
负责人：
Riti Sharan
金额：
$ 38.73万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-18 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10685926
关键词：
Affect Alveolar Macrophages Antiviral Therapy Automobile Driving Biological Markers Bronchoalveolar Lavage CD4 Positive T Lymphocytes Cell Lineage Cell physiology Cells Cessation of life Chronic Country Data Dendritic Cells Disease Event Freezing Funding HIV HIV Infections HIV/TB Healthcare Human Immune Immune response Immunologics Impairment Infection Innate Immune Response Interferon Type I Interferons Intervention K-Series Research Career Programs Lesion Link Lung Lung infections Macaca Macaca mulatta Macrophage Memory Mentored Research Scientist Development Award Modeling Mus Mycobacterium tuberculosis NK Cell Activation Natural Killer Cells Pathway interactions Phenotype Physiological Play Pre-Clinical Model Process Production Pulmonary Tuberculosis Research Resources Role SIV Sampling Shapes Structure of parenchyma of lung Study models T-Cell Depletion T-Lymphocyte Technology Therapeutic Tuberculosis Vaccine Design Viral Viremia Virus Virus Replication antiretroviral therapy archived data biomarker identification care burden co-infection cohort combinatorial data archive high risk immune activation imprint improved insight interstitial monocyte nonhuman primate pandemic disease predictive marker prevent response restoration sample archive single cell technology single-cell RNA sequencing synergism targeted treatment transcriptome transcriptomics

项目摘要

Project Summary The global control of tuberculosis (TB) is compounded by co-infection with Human Immunodeficiency Virus (HIV). Those infected with HIV are at high risk of reactivating latent TB infection (LTBI). Viral-induced chronic immune activation rather than mere depletion of CD4+ T cells correlates with LTBI reactivation due to SIV co-infection. Further, combinatorial antiretroviral therapy (cART) fails to restore T-effector functions and thus prevent LTBI reactivation in a nonhuman primate model of TB/SIV co-infection. Investigating the impact of cART on chronic immune activation in a relevant co-infected preclinical model at the single cell level will lead to the identification of key biomarkers predicting LTBI reactivation. We will synergize the research proposed here with a funded K01-award aims to collect cohesive data from archived control samples (uninfected, LTBI, SIV infected, Mtb/SIV co-infected but cART naïve; archived samples) and Mtb/SIV co-infected short-term, long-term cART treated (K-award) rhesus macaques. Based on our findings from the co-infection study, we hypothesize that while initiating cART at peak viremia in Mtb/SIV co- infection causes a significant decline in immune activation and macrophage turnover, it fails to rescue the skewed CD4+T effector memory responses leading to LTBI reactivation. Thus, in Aim 1, we will identify the specific lineage markers in the interplay between macrophages and CD4+ T cells that remain impaired despite cART in Mtb/SIV co-infected rhesus macaques. In Aim 2, we will investigate the earliest events of SIV-driven chronic immune activation and compare our findings to cART treated cohorts. For this, i) we will compare the activation status of plasmacytoid dendritic cells (pDCs) and NK cells in Mtb/SIV co-infection, ii) we will study the impact of cART on plasmacytoid dendritic cell (pDC)-driven Type-I Interferon (IFN) production and its impact on downstream effector responses compared to untreated controls. Overall, we will be able to determine if i) macrophage turnover interferes with CD4+ T cell restoration and function, ii) if cART effectively controls the earliest events of virus-driven immune activation by improving NK cell function and iii) the impact of cART on Type-I IFN response in driving the immune activation in Mtb/SIV co- infection. Studying the impact of cART on immune activation in Mtb/SIV co-infection is critical to identifying biomarkers for therapeutics and vaccine design to prevent LTBI reactivation.

项目概要结核病 (TB) 的全球控制因人类免疫缺陷病毒 (HIV) 的共同感染而变得更加复杂。 HIV 感染者重新激活潜伏性结核感染 (LTBI) 的风险很高。 CD4+ T 细胞的激活而非单纯的耗竭与 SIV 合并感染导致的 LTBI 重新激活相关。此外，组合抗逆转录病毒疗法 (cART) 无法恢复 T 效应器功能，从而预防 LTBI TB/SIV 混合感染的非人灵长类动物模型中的重新激活研究 cART 对慢性的影响。在单细胞水平的相关共感染临床前模型中的免疫激活将导致识别预测 LTBI 再激活的关键生物标志物。我们将把此处提出的研究与受资助的 K01 奖相结合，旨在收集有凝聚力的数据来自存档的对照样本（未感染、LTBI、SIV 感染、Mtb/SIV 共同感染但未使用 cART；已存档样本）和 Mtb/SIV 共同感染的短期、长期 cART 治疗（K 奖）恒河猴。根据我们的共同感染研究的结果，我们发现，在 Mtb/SIV 共同感染的病毒血症高峰时启动 cART 时，感染会导致免疫激活和巨噬细胞更新显着下降，但它无法挽救扭曲的局面 CD4+T 效应记忆反应导致 LTBI 重新激活，因此，在目标 1 中，我们将确定具体的机制。尽管 cART 治疗，巨噬细胞和 CD4+ T 细胞之间相互作用的谱系标记仍然受损 Mtb/SIV 共同感染的恒河猴在目标 2 中，我们将调查 SIV 驱动的慢性病的最早事件。免疫激活并将我们的发现与 cART 治疗组进行比较为此，i) 我们将比较激活。 Mtb/SIV 联合感染中浆细胞样树突状细胞 (pDC) 和 NK 细胞的状态，ii) 我们将研究 cART 对浆细胞样树突状细胞 (pDC) 驱动的 I 型干扰素 (IFN) 产生及其影响与未处理的对照相比，下游效应器反应。总的来说，我们将能够确定 i) 巨噬细胞周转是否会干扰 CD4+ T 细胞的恢复和功能，ii) cART 是否通过改善 NK 细胞有效控制病毒驱动的免疫激活的最早事件功能和 iii) cART 对 I 型 IFN 反应的影响，以驱动 Mtb/SIV 共生免疫激活研究 cART 对 Mtb/SIV 合并感染中免疫激活的影响对于识别 Mtb/SIV 感染至关重要。用于预防 LTBI 重新激活的治疗和疫苗设计的生物标志物。