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

• 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
• 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

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.

项目摘要 结核病（TB）的全球控制是通过与人类免疫缺陷病毒（HIV）共感染复合的。 感染HIV的人有重新激活潜在结核病感染（LTBI）的高风险。病毒诱导的慢性免疫 CD4+ T细胞的激活而不是仅仅耗尽与SIV共感染引起的LTBI重新激活相关。 此外，组合抗逆转录病毒疗法（CART）未能恢复T-效应功能，从而预防LTBI 在TB/SIV共感染的非人类私有模型中重新激活。调查购物车对慢性的影响 相关共感染的临床前模型中的免疫激活将导致鉴定 预测LTBI重新激活的关键生物标志物。 我们将在这里提出的研究协同作用，以收集凝聚力数据 来自存档的对照样品（未感染的LTBI，感染的LTBI，MTB/SIV共感染但幼稚；存档 样品）和MTB/SIV共感染的短期，长期治疗（K-award）恒河猕猴。基于 我们从共同感染研究中的发现，我们假设在MTB/SIV共同的峰值病毒血症中引发购物车时 感染会导致免疫激活和巨噬细胞周转率显着下降，无法挽救偏斜 CD4+T效应存储器响应导致LTBI重新激活。在AIM 1中，我们将确定特定的 巨噬细胞和CD4+ T细胞之间的相互作用中的谱系标记仍然受损 MTB/SIV共感染的恒河猕猴。在AIM 2中，我们将调查SIV驱动的慢性事件的最早事件 免疫激活并将我们的发现与手推车处理的队列进行比较。为此，i）我们将比较激活 MTB/SIV共同感染中质细胞囊细胞树突状细胞（PDC）和NK细胞的状态，ii）我们将研究 链球菌树突状细胞（PDC）驱动的I型干扰素（IFN）生产及其对其对影响的影响 与未处理的对照相比，下游效应子响应。 总体而言，我们将能够确定i）巨噬细胞的交换干扰CD4+ T细胞恢复和 功能，ii）如果购物车通过改善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MTB/SIV共同驱动免疫激活的I型IFN响应的影响 感染。研究购物车对MTB/SIV共感染中免疫激活的影响对于鉴定 用于预防LTBI重新激活的治疗和疫苗设计的生物标志物。