Persistent DNA Hyper-Methylation of the IFN-γ Signaling Pathway During Tuberculosis

结核病期间 IFN-γ 信号通路的持续 DNA 高甲基化

基本信息

批准号：
10408758
负责人：
Andrew R DiNardo
金额：
$ 18.93万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-20 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408758
关键词：
Aberrant DNA Methylation Adult Antigen Presentation Azacitidine Bioinformatics Biological Assay CXCL10 gene Cancer Patient Caring Case Fatality Rates Cells Cessation of life Classification Clinical Communicable Diseases Country DNA DNA Methylation DNA Sequence Alteration Data Defect Diagnosis Disease Epigenetic Process FRAP1 gene Foundations Funding Gene Chips Gene Expression Gene Expression Profile Genetic Glean Household Hypermethylation IFNGR1 gene IRF1 gene Immune Immune system Immunity Immunosuppression Immunotherapy In Vitro Individual Interferon Type II JAK1 gene Lymphocyte Malignant Neoplasms Maps Mentors Mentorship Methylation Monitor Multidrug-Resistant Tuberculosis Mutation Mycobacterium tuberculosis Oncology Outcome Participant Pathology Pathway Analysis Pathway interactions Patients Pharmacology Phenotype Phosphorylation Physiological Predisposition Production Prognosis Prognostic Marker Pulmonary Tuberculosis Research Personnel Risk STAT1 gene Sampling Science Scourge Signal Pathway Signal Transduction Supervision Testing Translating Treatment Efficacy Treatment Failure Tuberculosis base biobank bioinformatics tool cancer cell cytokine epigenetic regulation epigenetic therapy epigenomics improved improved outcome in vitro Assay in vivo inducible gene expression latent infection monocyte mortality mycobacterial novel pathogen practical application predictive signature prognostic promoter rare genetic disorder receptor success tool tool development transcription factor treatment duration tuberculosis treatment

项目摘要

PROJECT SUMMARY: Tuberculosis (TB) is the world’s leading infectious disease cause of mortality and suffering. Existing “short-course” therapy lasts six grueling months and has case fatality rates of 3% that increase to >20% in TB hyper-endemic countries and > 30% in the setting of multi-drug resistant TB. The Mendelian Susceptibility to Mycobacterial Disease (MSMDs) are rare genetic mutations that perturb the immune system either up or down-stream of the IFN-γ signaling pathway. It is well known that TB subverts host immune control, however the multiple mechanisms it does so remain to be fully elucidated. Our preliminary data demonstrate that TB epigenetically subverts host immunity by inducing DNA hyper-methylation both up and down-stream of the IFN-γ signaling pathway, akin to the MSMD mutations. Further, our preliminary data demonstrates that immune cells from study participants with TB have decreased up-regulate of IFN-γ-inducible gene expression, thereby mimicking the functional defect seen in the down-stream MSMD mutations in IFNGR, STAT1, and IRF1. Our preliminary bioinformatics analysis demonstrates that the inhibition of IFN-γ-inducible gene expression occurs through epigenetic inhibition of a) the canonical IFN-γ signaling pathway, b) transcription factors and c) non-canonical signaling pathways. Using an existing biorepository, we will evaluate the DNA methylation of the canonical IFN-γ signaling pathway as well as overlapping and intertwined non-canonical signaling pathways. We will functionally validate these results by evaluating if de-methylating agents are able to reverse DNA hyper-methylation of the IFN-γ signaling pathway and restore IFN-γ inducible gene expression. We will longitudinally perform these analyses on adults with 1) asymptomatic household contacts, 2) pulmonary TB with treatment success and 3) pulmonary TB with treatment failure. The elucidation of epigenetic mechanisms by which TB subverts host immunity is a necessary step in developing improved treatment monitoring tools and the development of adjunct host directed immunotherapy to improve clinical outcomes. The proposed science and mentorship will have the applicant poised for successful transition to an independent researcher.

项目摘要：结核病（TB）是世界领先的传染病导致死亡和痛苦的原因。现有的“短期”疗法持续六个月艰苦的月份，病例死亡率为3％，增加在结核病较高的国家中，在多药耐药结核病的情况下，达到20％。这孟德尔对分枝杆菌疾病（MSMD）的敏感性是罕见的遗传突变，扰动 IFN-γ信号通路的上或下游免疫系统。众所周知，结核病颠覆宿主免疫控制，但是多种机制仍然是完全的阐明。我们的初步数据表明，结核病表观遗传通过诱导颠覆了宿主的免疫力 IFN-γ信号通路的DNA高甲基化都向上和下游，类似于MSMD 突变。此外，我们的初步数据表明，来自研究参与者的免疫细胞 TB改善了IFN-γ诱导基因表达的上调，从而模仿了功能在IFNGR，STAT1和IRF1中的下游MSMD突变中看到的缺陷。我们的初步生物信息学分析表明，发生IFN-γ诱导基因表达的抑制作用发生通过表观遗传学抑制a）规范IFN-γ信号通路，b）转录因子和c）非典型信号通路。使用现有的生物座席，我们将评估规范IFN-γ的DNA甲基化信号通路以及重叠和交织的非人道信号通路。我们将通过评估脱甲基化剂能够逆转DNA来验证这些结果 IFN-γ信号通路的高甲基化并恢复IFN-γ诱导基因表达。我们将纵向对具有1）无症状家庭接触的成年人进行这些分析，2）肺结核病和治疗成功和3）肺结核具有治疗衰竭。阐明TB颠覆宿主免疫的表观遗传机制是必要的开发改进的治疗监控工具和开发辅助主机指示的步骤免疫疗法改善临床结局。拟议的科学和心态将具有申请人中毒成功地过渡到独立研究人员。