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: 10356911
• 负责人: Benjamin David Singer
• 金额: $ 50.13万
• 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/10356911
• 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; 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; Mediating; Morbidity - disease rate; Mus; Pathway interactions; Patients; 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; 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 全球每年有多达65万人死于季节性流感。甲型流感病毒 损伤肺部导致急性呼吸窘迫综合征(ARDS)。甲型流感病毒致急性呼吸窘迫综合征 尽管在抗病毒治疗和支持性护理方面取得了进展，但死亡率接近40%，大多数 患者在从最初的感染中恢复时会出现重症监护病房(ICU)并发症。在老鼠身上， 失调性修复导致广泛而持久的肺泡上皮异常 甲型流感我们的理由是，在严重流感康复期间激活修复通路将缩短 患者需要ICU的持续时间，从而降低ICU的随之而来的发病率和死亡率。 CD4+Foxp3+调节性T(Treg)细胞需要协调肺部炎症的消退和修复 小鼠模型的肺损伤。这些细胞出现在ARDS患者的肺泡间隙并显示 由小鼠实验预测的表观遗传学和转录图谱。在受损的肺中，Treg细胞施加 无数的促恢复功能，包括产生亲上皮分子，如两性调节素，丢失 这会加重甲型流感引起的小鼠急性肺损伤。在Treg细胞内，DNA甲基化模式在 特定的基因组基因座控制着它们的身份和抑制功能。表观遗传调节蛋白uhrf1发挥作用 在维持细胞类型特定的DNA甲基化特征方面起着至关重要的作用。UHRF1在中国的必要性 在甲型流感恢复期维持Treg细胞的特性和促进修复的功能仍不清楚。 同样，在恢复期，两亲调节素在诱导健康的上皮修复中的必要性也是必要的 未定义。我们假设Treg细胞需要uhrf1来维持其促修复功能，并且 在严重甲型流感病毒感染的康复过程中，双调节素能诱导上皮修复。我们 提出三个具体目标，它们使用创新的方法来验证我们的假设，包括尖端 小鼠系统，新的计算平台，以及将翻译我们的发现的人类病例对照研究 到床边去。目标1将确定uhrf1是否是维持Treg细胞转录程序所必需的 以及在甲型流感康复过程中的修复功能目标2将确定Treg细胞产生的必要性 双调蛋白在甲型流感所致肺损伤恢复过程中的促进修复作用。目标3将决定 肺泡Treg细胞的转录和表观遗传特征是否与30天死亡率有关 入选的重症病毒性肺炎患者。我们的提案将建立与毒品有关的因果证据- 有针对性的机制，以详细的生理读数。阐明这些因果联系将使 为严重流感和ARDS的其他原因开发促进康复的治疗方法。