Epigenetic Mechanism Reprogramming Mucosal Anti-viral Immunity in Allergic Asthma

过敏性哮喘粘膜抗病毒免疫的表观遗传机制重编程

• 批准号: 10371977
• 负责人: Allan R. Brasier
• 金额: $ 68.24万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-10 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371977
• 关键词: Adult; Affect; Air; Airway Disease; Allergens; Allergic rhinitis; Antiviral Response; Asthma; Binding; Biopsy; Blocking Antibodies; CD8-Positive T-Lymphocytes; Cells; Chronic; Coculture Techniques; Complex; Data; EP300 gene; Enhancers; Eosinophilia; Epigenetic Process; Epithelial; Epithelial Cells; Extracellular Matrix; Extrinsic asthma; FDA approved; Felis catus; Healthcare; Homeobox; Host Defense; Human; Human Volunteers; Hypersensitivity; ICAM1 gene; IRF1 gene; Impairment; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Injury; Interferons; Kinetics; Knowledge; Leukocytes; Liquid substance; Lymphocyte; Malignant neoplasm of lung; Measures; Mediating; Mediator of activation protein; Metaplasia; Methyltransferase; Modeling; Modification; Mucosal Immunity; Mucous Membrane; Mucous body substance; Mus; Nose; Nuclear; Organoids; Pathogenesis; Pathway interactions; Patients; Phase; Play; Population; Production; Quality of life; Recombinants; Relapse; Rhinovirus; Rhinovirus infection; Role; Running; Signal Transduction; System; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Time; Transforming Growth Factor beta; Transgenic Mice; Up-Regulation; Validation; Viral; Virus Diseases; Zinc Fingers; airborne allergen; airway hyperresponsiveness; airway remodeling; antiviral immunity; asthmatic; atopy; chemokine; chromatin immunoprecipitation; chronic inflammatory disease; clinically significant; cytokine; dander; eosinophil; epigenetic silencing; histone acetyltransferase; histone methyltransferase; immune function; immunoregulation; in vivo; inhibitor; mouse model; paracrine; pembrolizumab; preservation; programmed cell death ligand 1; promoter; pulmonary function; recruit; research clinical testing; respiratory infection virus; response; small molecule inhibitor; transcription factor; volunteer

PROJECT SUMMARY/ABSTRACT Rhinovirus (RV) infections are the most common causes of exacerbations in adults with allergic asthma (AA). Patients with AA have dysregulated type III interferon (IFNL) and T cell responses to infection, impairing viral clearance. We have found that allergen exposures silence the epithelial IFN regulatory factor (IRF)1- IFNL antiviral response and activate expression of the T cell co-inhibitor programmed death ligand (PDL)-1/B7H1. Our data implicate the Zinc Finger E box (ZEB1) transcription factor in mediating this epigenetic reprogramming by binding histone methyltransferase (EZH2) and histone acetyltransferase (p300/CBP) in a promoter-specific context. We will test the hypothesis that epithelial ZEB1 is induced by TGFβ signals produced by innate-induced remodeling and maintained by immunomodulatory eosinophil action. The epigenetic actions of ZEB1 silence the IRF1-IFNL response yet upregulate PDL1 to suppress CD8 T cell activation by recruitment of distinct histone acetyltransferases in specific promoter contexts. Our aims are to: 1. Determine the mechanism how ZEB1 induces epigenetic silencing of the IRF1-IFNL anti-viral pathway by allergen-and eosinophil-immunomodulation. We will examine the effect of ZEB1-EZH2 silencing on epigenetic modifications of the IRF1 enhancer/promoter in normal and AA epithelial cells (hAECs) by precision nuclear run-on (PRO-Seq) and chromatin immunoprecipitation. We will examine the role of ZEB- EZH2 in eosinophil-modulated suppression of IFNL responses in primary eosinophil co-cultures. These pathways will be probed in vivo by human ICAM1 transgenic mice with or without CDE remodeling upon RV infection. We expect the defective IRF/IFNL response will be reversed with ZEB1-EZH2 silencing. 2. Elucidate the mechanism how ZEB1 upregulates mucosal PD-L1 expression and determine its effects on CD8 T cell tolerance, RV clearance and AHR. RV-induced expression of PD-L1 will be measured in primary hAECs after silencing ZEB1-p300/CBP pathway. The effect of PDL1 on CD8-T cell suppression will be tested in co- culture systems using primary human T cells. We will test the role of PD-L1 in RV clearance in the hICAM1 transgenic mouse model using blocking antibodies (Abs) and validate the upregulation of PD-L1 in bronchial biopsies of AAs vs normal controls. We expect that PD-L1 inhibition will enhance CD8+ T cell activation and block AHR. 3. Test the effects of RV16 infection on mucosal IFNL and PD-L1 expression in human volunteers with or without allergen induced remodeling. We will recruit volunteers with eosinophilic AAs, allergic rhinitis (AR) and normal controls. We will test the relationship between remodeling induced IRF1/IFNL and PD-L1 expression in response to infection with recombinant RV16. We expect that IRF1-IFNL response and CD8+T cell response will be blunted in AAs with active remodeling. This project will significantly advance our understanding of the epigenetic control of mucosal immunity and provide new strategies to restore normal mucosal innate defenses in AA.

项目总结/文摘