Post-TB epigenetic scars' impact on long-term inflammation, immunity and mortality

结核病后表观遗传疤痕对长期炎症、免疫力和死亡率的影响

• 批准号: 10735471
• 负责人: Andrew R DiNardo
• 金额: $ 75.92万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735471
• 关键词: Age; Aging; Animal Model; Antigens; Antimycobacterial Agents; Automobile Driving; Bioinformatics; CD34 gene; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cavia; Cells; Cessation of life; Chronic; Cicatrix; Citric Acid Cycle; Clinical; Country; Cytomegalovirus; DNA; DNA Methylation; Data; Development; Diagnosis; Enrollment; Enzymes; Epigenetic Process; Gene Expression; Genes; Glean; HIV; Hematopoietic stem cells; Homeostasis; Human; Hypermethylation; Immune; Immune Tolerance; Immunity; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory; Interferons; Interleukin-6; Intervention; Knowledge; Life; Link; Lymphocytic choriomeningitis virus; Malignant Neoplasms; Measures; Mediating; Metabolic Pathway; Metformin; Methylation; Modeling; Molecular; Morbidity - disease rate; Outcome; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase II Clinical Trials; Population; Principal Component Analysis; Publications; Recurrence; Resources; Risk; SDZ RAD; Schistosomiasis; Signal Pathway; Succinates; Survivors; T-Lymphocyte; TNF gene; Techniques; Testing; Translating; Translational Research; Treatment Efficacy; Tricarboxylic Acids; Tuberculosis; Work; chronic infection; clinically relevant; cofactor; cohort; epigenomics; exhaust; guinea pig model; immune function; improved; in vivo; inhibitor; mortality; mouse model; mycobacterial; patient retention; practical application; premature; progenitor; sex; stem cells; support vector machine; transcriptome sequencing; tuberculosis treatment

PROJECT SUMMARY: After apparently successful treatment, Tuberculosis (TB) survivors have a 16.9% of death, a rate 3-fold higher than age and sex matched controls. In our previous work, we identified that six months after the completion of successful TB therapy, survivors retained detrimental epigenetic scars that continue to perturb host immunity and inflammation. In this proposal, using currently enrolling cohorts, we will test our proposal that these detrimental epigenetic scars induce pathologic inflammation and decrease immune responsiveness, leading to increased risk of post-TB mortality. Our previous work demonstrated that TB induces more than a thousand DNA methylation perturbations in pathways related to inflammation, TNF, IL-6 and IFN signaling pathways. Functionally, these DNA methylation perturbations are associated with increased inflammation and decreased immune responsiveness. Other infections (HIV, CMV, schistosomiasis) also induce long-lasting epigenetic scars, yet, to date, no study has identified which of these epigenetic scars are associated with post-TB mortality. Therefore, in Aim 1, we will follow TB patients for 30 months after completion of successful therapy to identify which DNA methylation marks are associated with post-TB mortality. While most immune cells only live a few days or weeks, our previous work demonstrated that DNA methylation perturbations persist at least 6 months after successful therapy. Animal models and our preliminary data support the hypothesis that detrimental epigenetic scars occur in progenitor and stem cells. To test this hypothesis, we will use cutting-edge single cell epigenomic (scATAC) and transcriptomics (scRNA) sequencing and pseudotime bioinformatic techniques to link progenitor exhausted populations with terminally exhausted populations. Our in vitro preliminary data, demonstrate that activation of the TCA metabolic pathway mediates the induction of detrimental epigenetic marks and that inhibiting the TCA activation can mitigate infection induced DNA hyper-methylation and restore immune responsiveness. Therefore, using our established guinea pig TB model, we will evaluate if inhibitors of the TCA cycle can block or reverse detrimental epigenetic scars and restore mycobacterial immunity. The elucidation of the specific epigenetic marks that subvert immune homeostasis and increase the risk of post-TB mortality is a necessary step in the development of adjunctive host directed therapy to decrease the current high mortality rates that occur after successful TB therapy.

项目概要： 经过明显成功的治疗后，结核病 (TB) 幸存者的死亡率为 16.9%，死亡率是原来的 3 倍 高于年龄和性别匹配的对照组。在我们之前的工作中，我们发现六个月后 成功完成结核病治疗后，幸存者保留了有害的表观遗传疤痕，并继续困扰 宿主免疫和炎症。在此提案中，我们将使用当前注册的队列来测试我们的提案 这些有害的表观遗传疤痕会诱发病理性炎症并降低免疫反应， 导致结核病后死亡风险增加。 我们之前的工作表明，结核病会诱发超过一千种 DNA 甲基化扰动 与炎症、TNF、IL-6 和 IFN 信号通路相关的通路。从功能上来说，这些DNA 甲基化扰动与炎症增加和免疫反应性降低有关。 其他感染（HIV、CMV、血吸虫病）也会引起持久的表观遗传疤痕，但迄今为止，尚无研究 已经确定了哪些表观遗传疤痕与结核病后死亡率相关。因此，在目标 1 中，我们 将在成功治疗完成后跟踪结核病患者 30 个月，以确定哪些 DNA 甲基化 标记与结核病后死亡率相关。 虽然大多数免疫细胞只能存活几天或几周，但我们之前的工作表明 DNA 成功治疗后甲基化扰动至少持续 6 个月。动物模型和我们的 初步数据支持这样的假设：有害的表观遗传疤痕发生在祖细胞和干细胞中。到 检验这个假设，我们将使用尖端的单细胞表观基因组学 (scATAC) 和转录组学 (scRNA) 测序和伪时间生物信息技术将祖细胞耗尽群体与终末期联系起来 疲惫不堪的人群。 我们的体外初步数据表明，TCA 代谢途径的激活介导 诱导有害的表观遗传标记，抑制 TCA 激活可以减轻诱导的感染 DNA 超甲基化并恢复免疫反应。因此，使用我们建立的豚鼠结核病 模型中，我们将评估 TCA 循环抑制剂是否可以阻止或逆转有害的表观遗传疤痕，以及 恢复分枝杆菌免疫力。阐明破坏免疫的特定表观遗传标记 体内平衡和增加结核病后死亡的风险是开发辅助药物的必要步骤 宿主定向治疗，以降低成功结核病治疗后目前出现的高死亡率。