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：
10624438
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/10624438
关键词：
Aberrant DNA Methylation Adult Antigen Presentation Azacitidine Bioinformatics Biological Assay CXCL10 gene Cancer Patient Cancer cell line Caring Case Fatality Rates Cells Cessation of life Classification Clinical Communicable Diseases Country DNA DNA Methylation DNA Sequence Alteration Data Defect Development Diagnosis Disease Epigenetic Process FRAP1 gene Foundations Funding Gene Chips Gene Expression Gene Expression Profile Genetic Glean Household Hypermethylation IFN Gamma Signaling Pathway 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 Phenotype Phosphorylation Physiological Prediction of Response to Therapy Predisposition Production Prognosis Prognostic Marker Pulmonary Tuberculosis Research Personnel STAT1 gene Sampling Science Scourge Signal Pathway Signal Transduction Testing Translating Treatment Efficacy Treatment Failure Tuberculosis biobank bioinformatics tool cytokine demethylation epigenetic drug epigenetic regulation epigenetic therapy epigenomics functional mimics improved improved outcome in vitro Assay in vivo inducible gene expression latent infection monocyte mortality mycobacterial novel pathogen pharmacologic practical application predictive signature progression risk promoter rare genetic disorder receptor success tool 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.

项目概要：结核病 (TB) 是世界上导致死亡和痛苦的主要传染病。现有的“短程”疗法需要持续 6 个月，病死率高达 3%，而且还会增加在结核病高流行国家，该比例可达 >20%；在多重耐药结核病环境中，该比例可达 >30%。孟德尔对分枝杆菌疾病 (MSMD) 的易感性是一种罕见的基因突变，会扰乱众所周知，结核病是免疫系统中 IFN-γ 信号通路的上游或下游。颠覆宿主的免疫控制，但它的多种机制仍有待充分研究阐明了。我们的初步数据表明，结核病通过诱导表观遗传学破坏宿主免疫力 IFN-γ 信号通路上游和下游的 DNA 高甲基化，类似于 MSMD 此外，我们的初步数据表明，来自研究参与者的免疫细胞具有突变。 TB 降低了 IFN-γ 诱导基因表达的上调，从而模仿了功能性我们初步发现，IFNGR、STAT1 和 IRF1 的下游 MSMD 突变存在缺陷。生物信息学分析表明，IFN-γ诱导基因表达受到抑制通过表观遗传抑制 a) 经典 IFN-γ 信号通路、b) 转录因子和 c) 非规范信号通路。使用现有的生物样本库，我们将评估经典 IFN-γ 的 DNA 甲基化信号通路以及重叠和交织的非规范信号通路。通过评估去甲基化剂是否能够逆转 DNA，从功能上验证这些结果我们将抑制 IFN-γ 信号通路的过度甲基化并恢复 IFN-γ 诱导基因的表达。对具有 1) 无症状家庭接触者、2) 肺部感染的成年人进行纵向分析治疗成功的结核病和 3) 治疗失败的肺结核。阐明结核病破坏宿主免疫的表观遗传机制是必要的开发改进的治疗监测工具和开发辅助宿主定向的步骤所提出的科学和指导将具有改善临床结果的免疫疗法。申请人成功转型为独立研究员。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Optimal Timing of Antiretroviral Therapy Initiation in Children and Adolescents With Human Immunodeficiency Virus-Associated Pulmonary Tuberculosis.

患有人类免疫缺陷病毒相关肺结核的儿童和青少年开始抗逆转录病毒治疗的最佳时机。

DOI：
发表时间：
2023-01-06
期刊：
影响因子：
0
作者：
Kay, Alexander;Mendez;Devezin, Tara;Bakaya, Meenakshi;Steffy, Teresa;Dlamini, Sandile;Msekandiana, Amos;Ness, Tara;Bacha, Jason;Amuge, Pauline;Matshaba, Mogomotsi;Chodota, Moses;Nyasulu, Phoebe;Thahane, Lineo;Mwita, Lumumbwa;Kek
通讯作者：
Kek

Optimizing DNA Extraction from Pediatric Stool for Diagnosis of Tuberculosis and Use in Next-Generation Sequencing Applications.

优化儿科粪便中的 DNA 提取以诊断结核病并用于下一代测序应用。

DOI：
发表时间：
2023-02-14
期刊：
影响因子：
3.7
作者：
Ness, Tara E;Meiwes, Lennard;Kay, Alexander;Mejia, Rojelio;Lange, Christoph;Farhat, Maha;Mandalakas, Anna;DiNardo, Andrew
通讯作者：
DiNardo, Andrew

human-associated microbiomes at an unprecedented scale. Together with a significant reduction in cost of sequencing technologies and development of advanced gene-editing tools, the potential of leveraging human-associated microbiome data for development of novel diagnostic and therapeutic tools

与人类相关的微生物组规模空前。

DOI：
10.26444/aaem/132452
发表时间：
2021-01-22
期刊：
Annals of agricultural and environmental medicine : AAEM
影响因子：
0
作者：
C. Loeffler;Keylie M. Gibson;Liz Chang;Jeremy Rotman;I. Toma;C. Mason;E. Eskin;J. Zackular;K. Cr;all;all;S. Mangul
通讯作者：
S. Mangul

Postinfectious Epigenetic Immune Modifications - A Double-Edged Sword.

感染后表观遗传免疫修饰——一把双刃剑。

DOI：
10.1056/nejmra2028358
发表时间：
2021-01-21
期刊：
The New England journal of medicine
影响因子：
0
作者：
DiNardo AR;Netea MG;Musher DM
通讯作者：
Musher DM

Perspectives for systems biology in the management of tuberculosis.

系统生物学在结核病治疗中的前景。

DOI：
发表时间：
2021-06-30
期刊：
影响因子：
0
作者：
Kontsevaya, Irina;Lange, Christoph;Comella;Coarfa, Cristian;DiNardo, Andrew R;Gillespie, Stephen H;Hauptmann, Matthias;Leschczyk, Christoph;Mandalakas, Anna M;Martinecz, Antal;Merker, Matthias;Niemann, Stefan;Reimann, Maja
通讯作者：
Reimann, Maja