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: 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
• 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

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.

项目摘要/摘要 呼吸综合病毒（RSV）是上呼吸道感染（LRTI）（LRTIS）的主要原因 寄主和免疫功能低下的宿主儿童，没有有效的治疗或疫苗。 患有RSV诱导的细支气管炎的儿童也有更高的旋转式风险和 晚年哮喘的发展。尽管RSV诱导的疾病的发病机理仍然是 激烈的科学辩论，越来越多的证据来自实验模型和自然收购的研究 感染表明，严重的LRTI确实与病毒“负载”和病毒延迟有关 由于先天免疫反应而导致的清除，该反应无法限制病毒复制，但会引起感染和 组织损伤。内源性生成的硫化氢（H2S）暗示在多种 炎症和血管疾病，与促炎和抗炎信号有关。最近， 我们的小组收集了重要的新数据，试剂和动物模型，这些模型证明了H2S的关键作用 肺中介导抗病毒和抗炎反应。特别是，我们已经证明了H2S 可能抑制病毒复制，执行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 胱淀粉γ-裂解酶（CSE），生成H2S的关键酶是肺，从而降低了产生的能力 细胞H2S。我们建议H2S途径的失调会影响宿主抗病毒反应，并发挥A 严重RSV感染的发病机理中的关键作用。我们的发现表明 H2S和转录因子NF-E2相关因子2（NRF2）依赖性途径，该途径控制细胞 氧化还原平衡，他们每个人都对另一方产生积极影响，他们俩都被下调 在RSV感染过程中。在这个项目中，我们将测试抑制的中心假设 细胞保护性H2S生成，由于精制NRF2依赖性基因转录，导致临床 RSV感染的表现。我们将采用体外和体内方法的组合来测试这一点 假设，通过在NRF2或H2S产生酶的NRF2或H2S中使用细胞和小鼠，以及 进入我们正在进行的婴儿和原发性RSV感染的幼儿队列的通道。这个项目将 阐明呼吸道病毒调节肺部病的先天途径，对 为RSV诱导的LRTI制定新型的抗病毒和抗炎治疗策略 长期后果，例如复发性的旋转或哮喘。我们长期存在的临床和研究 病毒触支炎和RSV感染的发病机理领域的专业知识，强烈的初步数据和 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性 项目。