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

表观遗传

• 批准号: 10385714
• 负责人: W. Henry Boom
• 金额: $ 108.01万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385714
• 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 Expression Profile; 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; insight; knockout gene; latent infection; macrophage; monocyte; novel; novel therapeutic intervention; 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的疫苗，预防 感染，长期的药物治疗方案和巨噬细胞中休眠的杆菌杀死。紧密联系后 对于患有肺结核的个体，大多数人会出现潜在的MTB感染（LTBI）。但是，有些 个体自然抗感染（RSTRS）。电阻的机制未知，可能 提供有关新型治疗策略的见解。在乌干达城市的大型TB家庭联系研究中 在过去的20年中，我们发现约有9％的成人家庭接触持续存在， 在扩展随访期间，干扰素-γ释放测定（IGRA）阴性。据我们所知，这个大乌干达 队列与严格的纵向临床和流行病学数据是独一无二的。使用基因元素富集和 RSTR中MTB感染的外周血衍生单核细胞的转录曲线的网络分析 和LTBI组，我们发现组蛋白脱乙酰基酶（HDAC）基因家族将RSTR与LTBIS区分开 并可能调节对MTB感染的抗性。我们在未感染的HIV-1中进​​行了全基因组连锁研究 （HIV-）乌干达的RSTR，发现与这种重要的临床表型相关的地方。在外围 血液单核细胞衍生和肺泡巨噬细胞，HDAC抑制剂治疗降低了MTB复制 与未处理的细胞进行比较。这些数据共同支持我们的主要假设，即RSTR具有 巨噬细胞依赖性且部分HDAC依赖性的保护性先天免疫反应。 但是，我们的知识有很多差距。首先，HDAC签名是基于网络的，我们确实 不知道它是否是RST型的主要因果调节剂。其次，HDAC是一个11人的家庭 修饰染色质并调节转录，细胞稳态和先天免疫的酶 对微生物的反应。在RSTR中改变了HDAC依赖性途径的细节是未知的。 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 艾滋病毒+个体中MTB的抗性是完全未知的。由于艾滋病毒感染极大地失去了t- 细胞对MTB的反应，感染HIV（HIV+）患者可能更多地取决于先天免疫力来帮助控制MTB 比未感染的艾滋病毒（HIV-）患者。在R61阶段（AIM 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方法 艾滋病毒+和艾滋病毒。在R33阶段（AIM 3），我们将使用细胞和体内方法来发现 这些途径的耐药机制和小分子抑制剂可以作为宿主发展 定向疗法。