Hydrogen Sulfide and NRF2 Cross-talk in Viral Infections

病毒感染中的硫化氢和 NRF2 串扰

基本信息

批准号：
9843442
负责人：
Antonella Casola
金额：
$ 50.38万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-11 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9843442
关键词：
3-Mercaptopyruvate sulfurtransferase Acetylation Acetylesterase Acute Affect Animal Model Anti-Inflammatory Agents Antioxidants Antiviral Agents Antiviral Response Area Asthma Bronchiolitis Cells Cessation of life Child Clinical Clinical Research Cystathionine Data Deacetylation Development Disease Elderly Enzymes Epithelial Cells Equilibrium Experimental Models Generations Genes Genetic Transcription Homeostasis Human Hydrogen Sulfide Immunocompromised Host In Vitro Infant Infection Inflammation Inflammatory Inflammatory Response Innate Immune Response Investigation Knock-out Laboratories Lead Link Lower Respiratory Tract Infection Lower respiratory tract structure Lung Lung Inflammation Lung diseases Lyase Mammals Mediating Mediator of activation protein Molecular Morbidity - disease rate Mus NF-E2-related factor 2 Nuclear Oxidation-Reduction Oxidative Stress Pathogenesis Pathway interactions Pharmacology Play Pneumonia Post-Translational Protein Processing Production Public Health Publishing Pulmonary Inflammation Reactive Oxygen Species Reagent Recurrence Reperfusion Injury Resources Respiratory Syncytial Virus Infections Respiratory Tract Diseases Respiratory Tract Infections Respiratory syncytial virus Risk Role Series Severities Severity of illness Shock Signal Transduction Sumoylation Pathway Syndrome Testing Therapeutic Tissues Ubiquitin Ubiquitination Vaccines Vascular Diseases Viral Viral Bronchiolitis Viral Load result Viral Pathogenesis Virus Virus Diseases Virus Replication Wheezing airway epithelium airway hyperresponsiveness antioxidant enzyme asthma exacerbation cell injury chemokine cohort cytokine disease phenotype effective therapy experience experimental study flu in vivo inducible gene expression innovation lung injury mortality mouse model multicatalytic endopeptidase complex novel novel therapeutic intervention nuclear factor-erythroid 2 prevent recruit replication stress respiratory morbidity respiratory virus response

项目摘要

PROJECT SUMMARY/ABSTRACT Respiratory syncytial virus (RSV) is a major cause of upper and lower respiratory tract infections (LRTIs) in children, elderly and immunocompromised hosts, for which no effective treatment or vaccine is available. Children who develop RSV-induced bronchiolitis are also at increased risk for recurrent wheezing and development of asthma in later life. Although the pathogenesis of RSV-induced disease remains a matter of intense scientific debate, increasing evidence from experimental models and studies in naturally acquired infections suggest that severe LRTIs are indeed associated with increased viral “load” and delayed viral clearance due to an innate immune response that fails to restrict viral replication, yet causing inflammation and tissue damage. The endogenously-generated gasotransmitter hydrogen sulfide (H2S) is implicated in a variety of inflammatory and vascular disorders, associated with both pro- and anti-inflammatory signaling. Recently, our group has gathered important new data, reagents and animals models that demonstrate a key role of H2S in mediating antiviral and anti-inflammatory responses in the lung. In particular, we have shown that H2S potently inhibits viral replication, exerts anti-inflammatory activity, and controls airway hyperresponsiveness in RSV-infected mice. At the cellular level, we have shown that RSV is capable of inhibiting the expression of cystathionine γ-lyase (CSE), the key enzyme that generates H2S is the lung, reducing the ability to generate cellular H2S. We propose that dysregulation of the H2S pathway affects host antiviral response and plays a critical role in the pathogenesis of severe RSV infections. Our findings indicate an important cross-talk between H2S and the transcription factor NF-E2-related factor 2 (NRF2)-dependent pathways, which control the cellular redox balance, each of them exerting a positive influence on the other, and both of them being downregulated in the course of RSV infection. Thus, in this project, we will test the central hypothesis that inhibition of cytoprotective H2S generation, due to decreased NRF2-dependent gene transcription, leads to clinical manifestations of RSV infection. We will employ a combination of in vitro and in vivo approaches to test this hypothesis, by the use of cells and mice genetically deficient in either NRF2 or H2S generating enzymes, and the access to our ongoing cohort of infants and young children with primary RSV infections. This project will elucidate innate pathways by which respiratory viruses modulate lung disease, with strong implications for developing novel antiviral and anti-inflammatory therapeutic strategies for RSV-induced LRTI and possibly long-term consequences, such as recurrent wheezing or asthma. Our long-standing clinical and research expertise in the area of pathogenesis of viral bronchiolitis and RSV infections, strong preliminary data, and UTMB's outstanding resources in the area of lung disease make us ideally suited to pursue this innovative project.

项目概要/摘要呼吸道合胞病毒（RSV）是引起上呼吸道和下呼吸道感染（LRTI）的主要原因儿童、老年人和免疫功能低下的宿主，目前尚无有效的治疗方法或疫苗。患有 RSV 诱发的细支气管炎的儿童反复喘息和喘息的风险也增加。尽管 RSV 引起的疾病的发病机制仍然是一个问题。激烈的科学争论，来自自然获得的实验模型和研究的证据越来越多感染表明，严重的 LRTI 确实与病毒“载量”增加和病毒传播延迟有关由于先天免疫反应无法限制病毒复制而导致的清除，但会引起炎症和内源性气体递质硫化氢 (H2S) 与多种组织损伤有关。最近，与促炎和抗炎信号相关的炎症和血管疾病。我们小组收集了重要的新数据、试剂和动物模型，证明了 H2S 的关键作用特别是，我们已经证明 H2S 能够介导肺部的抗病毒和抗炎反应。有效抑制病毒复制，发挥抗炎活性，并控制气道高反应性在细胞水平上，RSV 感染的小鼠能够抑制 RSV 的表达。胱硫醚γ-裂解酶（CSE），产生H2S的关键酶是肺，降低产生H2S的能力我们认为 H2S 通路的失调会影响宿主的抗病毒反应并发挥重要作用。我们的研究结果表明，RSV 感染之间存在重要的相互作用。 H2S 和转录因子 NF-E2 相关因子 2 (NRF2) 依赖性途径，控制细胞氧化还原平衡，两者都对对方产生积极影响，并且两者都被下调因此，在这个项目中，我们将测试抑制RSV的中心假设。由于 NRF2 依赖性基因转录减少，细胞保护性 H2S 的产生导致临床我们将结合体外和体内方法来测试 RSV 感染的表现。假设，通过使用基因上缺乏 NRF2 或 H2S 生成酶的细胞和小鼠，以及该项目将访问我们正在进行的原发性 RSV 感染婴儿和幼儿队列。阐明呼吸道病毒调节肺部疾病的先天途径，对开发针对 RSV 诱导的 LRTI 的新型抗病毒和抗炎治疗策略，并可能长期后果，例如反复喘息或哮喘。病毒性细支气管炎和RSV感染发病机制领域的专业知识、强有力的初步数据以及 UTMB 在肺部疾病领域的杰出资源使我们非常适合追求这一创新项目。