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: 10116463
• 负责人: Benjamin David Singer
• 金额: $ 50.36万
• 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/10116463
• 关键词: AREG gene; Acute; Acute Lung Injury; Adaptor Signaling Protein; Adult Respiratory Distress Syndrome; 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; Drug Targeting; Epigenetic Process; Epithelial; 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; Lung Inflammation; Mediating; Morbidity - disease rate; Mus; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiological; Play; Pneumonia; Protein Isoforms; Proteins; Publishing; Reagent; Recovery; Recovery of Function; Regulator Genes; Regulatory Element; Regulatory T-Lymphocyte; Research Infrastructure; Resolution; Risk; Role; 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; genomic locus; 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.

项目摘要/摘要 季节性影响与全球每年最多650,000例呼吸道死亡有关。流感病毒 伤害肺部导致急性呼吸窘迫综合征（ARDS）。流感A诱导的ARDS 在抗病毒疗法和支持性护理方面的死亡率接近40％的死亡率，大多数 患者从初始感染中恢复过来，屈服于重症监护病房（ICU）并发症。在老鼠中， 严重后，不调节修复导致宽度和持续性肺泡上皮异常 actractza A.我们认为，从严重影响力恢复过程中的维修途径的激活将缩短 患者需要ICU的时间持续时间，从而减轻ICU随之而来的发病率和死亡率。 CD4+ FOXP3+调节t（Treg）细胞需要协调肺注射和修复的分辨率 鼠标模型中的肺损伤。这些细胞出现在ARDS患者的肺泡空间中 通过鼠实验预测的表观遗传和转录谱。在受伤的肺中，Treg细胞运动 众多的促进功能，包括产生诸如两极蛋白等促生上皮分子，损失 这种恶化会影响小鼠A诱导的急性肺损伤。在Treg细胞中，DNA甲基化模式在 特定的基因组基因座控制其身份和抑制功能。表观遗传调节蛋白UHRF1播放 维持细胞类型特异性DNA甲基化特征的重要作用。 UHRF1的必要 在影响力的恢复阶段保持Treg细胞身份和促修复功能仍然未知。 同样，在恢复阶段诱导健康的上皮修复中的两极分裂蛋白的必要条件也是 不明确的。我们假设Treg细胞要求UHRF1维持其促进函数和 在严重影响中恢复病毒感染期间，两极蛋白会诱导上皮修复。我们 提案三个具体目标，使用创新方法来检验我们的假设，包括尖端 鼠系统，新颖的计算平台和人类病例对照研究，该研究将转化我们的发现 到床边。 AIM 1将确定UHRF1是否需要维护Treg单元转录程序 从影响力A. AIM 2恢复期间的促进功能将确定Treg细胞生成的必要 在促进影响ZA A诱导的肺损伤中促进修复过程中的两极分裂蛋白。 AIM 3将确定 肺泡Treg细胞中的转录和表观遗传学特征是否与30天死亡率有关 精选患有严重病毒性肺炎的患者。我们的提议将建立与药物联系联系的因果证据 - 详细的生理读数的目标机制。阐明这些因果关系将告知 开发针对严重影响力和其他ARDS原因的恢复治疗方法。