Hydrogen Sulfide and NRF2 Cross-talk in Viral Infections

病毒感染中的硫化氢和 NRF2 串扰

• 批准号: 10379874
• 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
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-11 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379874
• 关键词: 3-Mercaptopyruvate sulfurtransferase; Acetylation; Acetylesterase; Acute; Affect; Animal Model; Anti-Inflammatory Agents; Antioxidants; 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 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

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.

项目总结/摘要 呼吸道合胞病毒（RSV）是导致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，对此没有有效的治疗或疫苗。 患有RSV引起的细支气管炎的儿童也会增加反复喘息的风险， 哮喘在晚年的发展。尽管RSV引起的疾病的发病机制仍然是一个问题， 激烈的科学辩论，越来越多的证据来自实验模型和自然获得的研究。 感染表明，严重的LRTI确实与增加的病毒“负荷”和延迟的病毒感染有关。 由于先天免疫反应而导致的清除，不能限制病毒复制，但会引起炎症， 组织损伤内源性产生的气体递质硫化氢（H2S）与多种 炎症和血管疾病，与促炎和抗炎信号有关。最近， 我们的团队已经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 介导肺部的抗病毒和抗炎反应。特别是，我们已经表明，H2S 有效抑制病毒复制，发挥抗炎活性，并控制气道高反应性， RSV感染的小鼠。在细胞水平上，我们已经证明RSV能够抑制 胱硫醚γ-裂解酶（CSE），产生H2S的关键酶是肺，降低了产生H2S的能力。 细胞内H2S我们认为，H2S途径的失调影响宿主的抗病毒反应，并发挥作用。 在严重RSV感染的发病机制中起关键作用。我们的研究结果表明， H2S和转录因子NF-E2相关因子2（NRF 2）依赖性途径，这些途径控制细胞内 氧化还原平衡，它们中的每一个都对另一个产生积极的影响，并且它们都被下调 在RSV感染的过程中。因此，在这个项目中，我们将测试中心假设，即抑制 由于NRF 2依赖性基因转录减少，细胞保护性H2S生成导致临床 RSV感染的表现。我们将采用体外和体内相结合的方法来测试这一点 假设，通过使用在NRF 2或H2S生成酶中遗传缺陷的细胞和小鼠，以及 获得我们正在进行的患有原发性RSV感染的婴儿和幼儿队列。该项目将 阐明呼吸道病毒调节肺部疾病的先天途径， 为RSV诱导的LRTI开发新的抗病毒和抗炎治疗策略， 长期后果，如反复喘息或哮喘。我们长期的临床和研究 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