Mechanisms of regulatory T cell-mediated recovery from severe influenza A virus infection

调节性 T 细胞介导的严重甲型流感病毒感染恢复机制

• 批准号: 10586095
• 负责人: Benjamin David Singer
• 金额: $ 49.78万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586095
• 关键词: AREG gene; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adaptor Signaling Protein; Alveolar; Amphiregulin; Antiviral Agents; Antiviral Therapy; Back; Bronchoalveolar Lavage; Caring; Case/Control Studies; Cells; Cessation of life; Clinical Research; Control Locus; Critical Illness; Cytosine; DNA; DNA Binding; DNA Maintenance; DNA Methylation; DNA Modification Methylases; Data; Development; Epigenetic Process; Epithelium; FOXP3 gene; Flow Cytometry; Gene Expression Profile; Generations; Genetic Transcription; Growth Factor; Guanine; Human; Infection; Inflammation; Influenza; Influenza A virus; Intensive Care Units; Link; Lung; Mediating; Morbidity - disease rate; Mus; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Phase; Physiological; Play; Pneumonia; Protein Isoforms; Proteins; Publishing; Pulmonary Inflammation; Reagent; Recovery; Recovery of Function; Regulator Genes; Regulatory Element; Regulatory T-Lymphocyte; Research Infrastructure; Resolution; Risk; Role; Sorting; Supportive care; System; T-Lymphocyte Subsets; Technical Expertise; Testing; Therapeutic; Time; Tissues; Translating; Viral; Viral Pneumonia; Virus Diseases; Work; alveolar epithelium; cell type; computational platform; dimensional analysis; epithelial repair; experimental study; gene repair; gene repression; genomic locus; high dimensionality; influenza infection; innovation; lung injury; lung repair; methylation pattern; mortality; mouse model; novel; novel therapeutics; programs; recruit; repair function; repaired; respiratory; seasonal influenza

PROJECT SUMMARY/ABSTRACT Seasonal influenza is associated with up to 650,000 respiratory deaths per year worldwide. Influenza A virus injures the lung to cause the acute respiratory distress syndrome (ARDS). Influenza A virus-induced ARDS carries a mortality rate approaching 40% despite advances in anti-viral therapies and supportive care, with most patients succumbing to intensive care unit (ICU) complications as they recover from the initial infection. In mice, dysregulated repair leads to widespread and persistent alveolar epithelial abnormalities following severe influenza A. We reason that activation of repair pathways during recovery from severe influenza will shorten the duration of time that patients require the ICU, thus mitigating the ICU’s attendant morbidity and mortality. CD4+Foxp3+ regulatory T (Treg) cells are required to coordinate resolution of lung inflammation and repair of lung damage in mouse models. These cells appear in the alveolar spaces of patients with ARDS and display epigenetic and transcriptional profiles predicted by murine experiments. In the injured lung, Treg cells exert myriad pro-recovery functions, including generation of pro-epithelial molecules such as amphiregulin, the loss of which worsens influenza A-induced acute lung injury in mice. Within Treg cells, the DNA methylation pattern at specific genomic loci controls their identity and suppressive function. The epigenetic regulator protein Uhrf1 plays an essential role in maintaining cell type-specific DNA methylation signatures. The necessity of Uhrf1 in maintaining Treg cell identity and pro-repair function during the recovery phase of influenza A remains unknown. Likewise, the necessity of amphiregulin in inducing healthy epithelial repair during the recovery phase is also undefined. We hypothesize that Treg cells require Uhrf1 to maintain their pro-repair function and amphiregulin to induce epithelial repair during recovery from severe influenza A virus infection. We propose three Specific Aims, which use innovative approaches to test our hypothesis, including cutting-edge murine systems, novel computational platforms, and a human case-control study that will translate our findings to the bedside. Aim 1 will determine whether Uhrf1 is necessary to maintain Treg cell transcriptional programs and pro-repair function during recovery from influenza A. Aim 2 will ascertain the necessity of Treg cell-generated amphiregulin in promoting repair during recovery from influenza A-induced lung injury. Aim 3 will determine whether transcriptional and epigenetic signatures in alveolar Treg cells are associated with 30-day mortality in selected patients with severe viral pneumonia. Our proposal will establish causal evidence linking drug- targetable mechanisms to detailed physiologic readouts. Elucidating these causal links will inform the development of pro-recovery therapeutic approaches for severe influenza and other causes of ARDS.

项目总结/摘要 季节性流感与全世界每年多达650，000例呼吸道死亡有关。甲型流感病毒 损伤肺引起急性呼吸窘迫综合征（ARDS）。甲型流感病毒诱导的ARDS 尽管抗病毒治疗和支持性护理取得了进展，但死亡率仍接近40%， 患者在从初始感染中恢复时死于重症监护室（ICU）并发症。在小鼠中， 在严重的呼吸道感染后， 甲型流感我们推断，在从严重流感中恢复期间，修复途径的激活将缩短 患者需要ICU的持续时间，从而减轻ICU伴随的发病率和死亡率。 需要CD 4 + Foxp 3+调节性T（Treg）细胞来协调肺部炎症的消退和肺部炎症的修复。 小鼠模型中的肺损伤。这些细胞出现在ARDS患者的肺泡腔中， 通过小鼠实验预测的表观遗传和转录谱。在受伤的肺中，Treg细胞发挥作用， 无数的促恢复功能，包括产生促上皮分子如双调蛋白， 其对抗甲型流感诱导的小鼠急性肺损伤。在Treg细胞内，DNA甲基化模式在 特定的基因座控制它们的身份和抑制功能。表观遗传调节蛋白Uhrf 1发挥着 在维持细胞类型特异性DNA甲基化签名中起重要作用。Uhrf 1在 在甲型流感恢复阶段维持Treg细胞身份和促修复功能仍然未知。 同样，双调蛋白在恢复阶段诱导健康上皮修复的必要性也是 未定义。我们假设Treg细胞需要Uhrf 1来维持其促修复功能， 双调蛋白在从严重的甲型流感病毒感染恢复期间诱导上皮修复。我们 我提出了三个具体的目标，使用创新的方法来测试我们的假设，包括尖端的 鼠系统，新的计算平台，以及人类病例对照研究，将转化我们的发现 到床边目的1将确定Uhrf 1是否是维持Treg细胞转录程序所必需的 和促修复功能。目的2：明确Treg细胞体外诱导的必要性 双调蛋白在从甲型流感诱导的肺损伤恢复期间促进修复。目标3将决定 肺泡Treg细胞中的转录和表观遗传特征是否与30天死亡率相关， 选择重症病毒性肺炎患者。我们的建议将建立因果关系的证据连接毒品- 有针对性的机制，以详细的生理读数。阐明这些因果关系将告知 开发用于严重流感和其他原因的ARDS的促恢复治疗方法。