The role of innate immunity in downregulation of the airway antioxidant response during paramyxovirus infection

先天免疫在副粘病毒感染期间气道抗氧化反应下调中的作用

• 批准号: 10205990
• 负责人: Antonella Casola
• 金额: $ 47.4万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205990
• 关键词: Acetylation; Acetylesterase; Acute; Antioxidants; Antiviral Agents; Antiviral Response; Aspirate substance; Asthma; Blood; Bronchiolitis; Cells; Cessation of life; Child; Chromatin; Clinical; Collaborations; Data; Deacetylation; Development; Disease; Disease Outcome; Down-Regulation; Elderly; Enzyme Inhibition; Enzymes; Epithelial; Epithelial Cells; Family; Gene Expression; Genes; Genetic Transcription; Histone Deacetylase; Human; Immune; In Vitro; Infant; Infection; Inflammation; Inflammatory; Innate Immune Response; Interferon Type I; Interferons; Knock-out; Laboratories; Link; Lower Respiratory Tract Infection; Lung; Lung Inflammation; Lung diseases; Mediating; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Mus; NF-E2-related factor 2; Natural Immunity; Nose; Nuclear; Nuclear Protein; Oxidative Stress; Paramyxovirus; Pathogenesis; Pathway interactions; Phase; Phosphorylation Site; Play; Precipitation; Process; Production; Protein Isoforms; Proteins; Pulmonary Inflammation; Reactive Oxygen Species; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory syncytial virus; Response Elements; Role; Sampling; Series; Serine; Severities; Severity of illness; Signal Pathway; Signal Transduction; Site; Snails; Sumoylation Pathway; Testing; Therapeutic Intervention; Time; Tracheobronchial; Viral; Virus; Zinc Fingers; airway epithelium; airway inflammation; airway remodeling; antioxidant enzyme; asthma exacerbation; base; chemokine; cytokine; in vivo; inducible gene expression; lung injury; mortality; mouse model; multicatalytic endopeptidase complex; neutrophil; novel; novel therapeutic intervention; nuclear factor-erythroid 2; overexpression; oxidative damage; p65; programs; promoter; pulmonary function; recruit; respiratory morbidity; respiratory virus; response; targeted treatment; transcription factor; transcription factor PML; type I interferon receptor; ubiquitin ligase

PROJECT SUMMARY/ABSTRACT This application is focused on the paradoxical role of innate immune and antiviral responses in the dysregulation of critical cytoprotective responses in the lung. We have previously discovered that an unbalanced reactive oxygen species (ROS) production in the course of respiratory syncytial virus (RSV) infection, the major cause of lower respiratory tract infections (LRTI) in infants, is caused by a progressive reduction in nuclear and cellular levels of the transcription factor NF-E2-related factor 2 (NRF2), the primary regulator of antioxidant enzyme (AOE) gene expression. This process, which contributes to lung disease and inflammation, occurs through deacetylation and increased degradation of NRF2 via the proteasome pathway and leads to decreased expression of AOEs in RSV-infected airway epithelial cells (AECs), in experimental mice, as well as, in children with naturally acquired RSV LRTI. RSV-mediated NRF2 degradation occurs via the sumoylation-dependent ubiquitin ligase RNF4, which is recruited to the promyelocytic leukemia protein nuclear bodies (PML-NBs) in conditions of cellular oxidative stress. In the absence of IFN-dependent signaling, we found no induction of PML protein, a major component of PML-NBs, in response to RSV infection and significantly reduced NRF2 degradation, resulting in enhanced AOE gene expression. Moreover, mice lacking type I IFN receptor (IFNR1 -/-) display significant reduction of lung inflammation and overall improvement in clinical disease. RSV infection in infants and young children is known to be poorly responsive to the canonical antiviral activity of interferons (IFNs), whereas evidence of overexpression of IFN genes in lung and blood has been shown to be associated with immune dysregulation. In addition, preliminary studies indicated that lack of NF-κB activation revert RSV-induced decrease in NRF2 acetylation, restoring its cellular and nuclear levels, with subsequent increase in NRF2-dependent gene transcription and AOE gene expression. Based on these data, we will test the hypothesis that RSV-induced proinflammatory and antiviral pathways play a central role in the RSV-induced demise of NRF2, leading to lung oxidative injury and ROS-dependent disease pathogenesis. These studies will provide initial experimental evidence that modulation of the IFN pathway could represent a possible target for therapeutic intervention for RSV-induced oxidative lung damage and inflammation. .

项目摘要/摘要 该应用的重点是先天免疫和抗病毒反应在 肺中关键细胞保护反应的失调。我们以前已经发现 在呼吸综合病毒（RSV）过程中，不平衡的活性氧（ROS）产生 感染是婴儿下呼吸道感染（LRTI）的主要原因，是由进行的 转录因子NF-E2相关因子2（NRF2）的核和细胞水平降低，主要 抗氧化酶（AOE）基因表达的调节剂。这个过程，有助于肺部疾病和 炎症，通过脱乙酰基化和通过蛋白酶体途径增加NRF2的降解 并导致在RSV感染的气道上皮细胞（AEC）中改善AOE的表达 小鼠以及自然获得RSV LRTI的儿童。 RSV介导的NRF2降解是通过 依赖于sumoylation的泛素连接酶RNF4，该连接酶RNF4被募集到临床细胞性白血病蛋白 细胞氧化物应激条件下的核体（PML-NB）。在没有IFN依赖性信号的情况下， 我们发现响应RSV感染和 显着降低了NRF2降解，从而导致AOE基因表达增强。而且，老鼠缺乏 I型IFN受体（IFNR1 - / - ）显示出明显的肺注射和总体改善 临床疾病。众所周知，婴儿和幼儿的RSV感染对规范的反应很差 干扰素（IFN）的抗病毒活性，而肺和血液中IFN基因过度表达的证据 我们被证明与免疫失调有关。此外，初步研究表明缺乏 NF-κB激活恢复了RSV诱导的NRF2乙酰化的降低，恢复了其细胞和核水平， 随后NRF2依赖性基因转录和AOE基因表达的增加。基于这些 数据，我们将检验以下假设：RSV诱导的促炎和抗病毒途径在 RSV诱导的NRF2灭亡，导致肺氧化物损伤和ROS依赖性疾病发病机理。 这些研究将提供最初的实验证据，表明对IFN途径的调节可以代表 RSV诱导的氧化物肺损伤和炎症的热干预的可能目标。 。