Epigenetic & Post-Translational Mechanisms of Macrophage Resistance to Mycobacterium tuberculosis During HIV Co-Infection

表观遗传

• 批准号: 10092518
• 负责人: W. Henry Boom
• 金额: $ 102.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092518
• 关键词: Acetylation; Address; Adult; Alveolar; Alveolar Macrophages; Bacillus; Biological Assay; CRISPR/Cas technology; Candidate Disease Gene; Cells; Chromatin; Clinical Data; Data; Development; Enzymes; Epigenetic Process; Family; Gene Family; Genes; Genetic Transcription; Growth; HIV; HIV Infections; HIV resistance; HIV/TB; Histone Deacetylase; Histone Deacetylase Inhibitor; Homeostasis; Host resistance; Household; Human; Immunity; In Vitro; Individual; Infection; Infection prevention; Innate Immune Response; Interferons; Knock-out; Knowledge; Lead; Mediating; Microbe; Modeling; Mus; Mycobacterium tuberculosis; Natural Immunity; Natural Resistance; Network-based; Pathogenesis; Pathway Analysis; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Phosphorylation; Post-Translational Protein Processing; Proteins; Proteomics; Pulmonary Tuberculosis; Research Design; Resistance; Signal Transduction; T cell response; Testing; Treatment Protocols; Tuberculosis; Uganda; Vaccines; chromatin modification; clinical phenotype; co-infection; cohort; epidemiologic data; follow-up; genetic approach; genetic variant; genome-wide linkage; immunomodulatory therapies; in vivo; induced pluripotent stem cell; inhibitor/antagonist; insight; knockout gene; latent infection; macrophage; monocyte; novel; novel therapeutics; peripheral blood; resistance gene; resistance mechanism; small molecular inhibitor; small molecule inhibitor; treatment strategy

Hurdles for controlling tuberculosis (TB) include the lack of a highly efficacious vaccine, prevention of infection, long drug treatment regimens, and killing dormant bacilli within macrophages. After close contact with an individual with pulmonary TB, most people develop latent Mtb infection (LTBI). However, some individuals are naturally resistant to infection (RSTRs). The mechanisms of resistance are unknown and may provide insight into novel therapeutic strategies. In a large TB household contact study in urban Uganda over the past 20 years, we found that ~9% of close adult household contacts remained persistently TST and Interferon-γ Release Assay (IGRA) negative during extended follow-up. To our knowledge, this large Ugandan cohort is unique with rigorous longitudinal clinical and epidemiologic data. Using gene-set enrichment and network analyses of transcriptional profiles of Mtb-infected peripheral blood-derived monocytes in the RSTR and LTBI groups, we found that the histone deacetylase (HDAC) gene family distinguishes RSTRs from LTBIs and may regulate resistance to Mtb infection. We performed a genome-wide linkage study in HIV-1 uninfected (HIV-) RSTRs in Uganda and discovered loci associated with this important clinical phenotype. In peripheral blood monocyte-derived and alveolar macrophages, HDAC inhibitor treatment decreased Mtb replication in comparison to untreated cells. Together, these data support our primary hypotheses that RSTRs have protective innate immune responses that are macrophage-dependent and partially HDAC-dependent. However, there are many gaps in our knowledge. First, the HDAC signature was network-based and we do not know if it is the major causal regulator of the RSTR phenotype. Second, HDACs are a family of 11 enzymes which modify chromatin and regulate transcription, cellular homeostasis, and the innate immune response to microbes. The details of which HDAC-dependent pathways are altered in RSTRs are unknown. Epigenetic and proteomic studies (including acetylation profiles) can address these gaps. Third, mechanisms of Mtb resistance in HIV+ individuals are completely unknown. Since HIV infection profoundly dysregulates T- cell responses to Mtb, HIV infected (HIV+) persons likely depend more on innate immunity to help control Mtb than HIV uninfected (HIV-) persons. In the R61 phase (Aim 1 and 2), we will use epigenetic, proteomic, and genetic approaches to discover candidate resistance genes and pathways that differ between RSTR and LTBI HIV+ and HIV- individuals. In the R33 phase (Aim 3), we will use cellular and in vivo approaches to discover mechanisms of resistance and small molecular inhibitors of these pathways that could be developed as host directed therapies.

控制结核病 (TB) 的障碍包括缺乏高效疫苗、预防结核病 感染、长期药物治疗以及杀死巨噬细胞内的休眠杆菌。 大多数肺结核患者都会出现潜伏性结核菌感染 (LTBI)。 个体对感染有天然抵抗力（RSTR），抵抗机制尚不清楚，可能是这样。 在乌干达城市的一项大型结核病家庭接触研究中，提供了对新治疗策略的见解。 在过去 20 年中，我们发现约 9% 的密切成年家庭接触者持续存在 TST 和 据我们所知，这个大乌干达人在长期随访期间干扰素-γ释放测定（IGRA）呈阴性。 队列是独一无二的，具有严格的纵向临床和流行病学数据，并使用基因集富集和。 RSTR 中 Mtb 感染的外周血来源单核细胞转录谱的网络分析 和 LTBI 组，我们发现组蛋白脱乙酰酶 (HDAC) 基因家族将 RSTR 与 LTBI 区分开来 并可能调节对 Mtb 感染的抵抗力 我们在未感染 HIV-1 的人群中进行了全基因组连锁研究。 乌干达的 (HIV-) RSTR 并发现了与这一重要临床表型相关的位点。 血液单核细胞来源和肺泡巨噬细胞、HDAC 抑制剂治疗可减少 Mtb 复制 与未经处理的细胞进行比较，这些数据共同支持了我们的主要假设：RSTR 具有 保护性先天免疫反应依赖于巨噬细胞，部分依赖于 HDAC。 然而，我们的知识存在许多空白，首先，HDAC 签名是基于网络的，而我们确实如此。 不知道它是否是 RSTR 表型的主要因果调节因子 其次，HDAC 是一个由 11 个蛋白组成的家族。 修饰染色质并调节转录、细胞稳态和先天免疫系统的酶 RSTR 中哪些 HDAC 依赖性途径发生改变的细节尚不清楚。 表观遗传学和蛋白质组学研究（包括乙酰化谱）可以解决这些差距。第三，机制。 HIV+ 个体中的 Mtb 耐药性完全未知，因为 HIV 感染会严重失调 T-。 细胞对 Mtb 的反应，HIV 感染者 (HIV+) 可能更多地依赖于先天免疫来帮助控制 Mtb 在 R61 阶段（目标 1 和 2），我们将使用表观遗传学、蛋白质组学和 发现 RSTR 和 LTBI 之间不同的候选抗性基因和途径的遗传学方法 在 R33 阶段（目标 3），我们将使用细胞和体内方法来发现 HIV+ 和 HIV- 个体。 耐药机制和这些途径的小分子抑制剂可开发为宿主 定向治疗。