Mechanisms mediating tissue repair by leukocytes during influenza virus infection

项目摘要/摘要 季节性甲型流感病毒流行是一个顽固的全球卫生问题，会导致严重的疾病和 高危人群死亡。与其他呼吸道病毒感染一样，疾病的康复需要病原体 清除，消除抗病毒炎症反应，修复受损的肺组织。正在恢复 肺上皮屏障对器官生理学具有深远的意义，有必要尽量减少 对继发性细菌感染的易感性1，2.虽然许多研究都集中在病毒的不同阶段 通过先天和适应性免疫反应消除3，全面了解组织修复是如何进行的 协调，以及白细胞在这一过程中的作用，还没有明确的定义。 最近的研究证实了白细胞衍生的表皮生长因子受体的作用 (EGFR)配体，双调节素，在促进肠道和肌肉4，5及以下的组织保护中的作用 流感病毒诱导的肺损伤6，7。申请人最近说明了基因消融 小鼠调节性T(Treg)细胞中的双调节素导致肺功能受损和明显的气道减少 活体感染流感病毒后的上皮修复。转录图谱和流式细胞术 对感染后5天分离的小鼠肺Treg细胞的分析表明，这些细胞表达受体 两种标志性组织损伤细胞因子IL-18和IL-33以及对纯化的幼稚Treg细胞的体外治疗 这两种细胞因子中的任何一种都足以诱导双调节蛋白的产生。这些发现揭示了一种 Treg细胞衍生的双调节蛋白在维持上皮屏障中的重要作用 在对呼吸道病原体的免疫反应过程中保持完整性。这份K22建议书建立在申请人的 先前的研究和检查(1)Treg细胞来源的双调节蛋白对组织的贡献的机制 修复和(2)其他产生双调节蛋白的白细胞和组织保护性介质在 在整个流感感染过程中协调修复过程。 描述防止感染损伤和预防感染的分子和细胞途径 相关的免疫病理学将拓宽我们对免疫反应的了解，并有助于 治疗传染病、过敏性疾病和自身免疫性疾病的新疗法的发展。

PROJECT SUMMARY/ABSTRACT Seasonal influenza A virus epidemics are an obstinate global health issue and cause severe illness and death in high-risk populations. As with other respiratory viral infections, recovery from illness requires pathogen clearance, resolution of the anti-viral inflammatory response, and repair of damaged lung tissue. Restoring the pulmonary epithelial barrier is of profound importance to organ physiology and necessary to minimize susceptibility to secondary bacterial infections1, 2. While many studies have focused on the stages of viral elimination by innate and adaptive immune responses3, a comprehensive understanding of how tissue repair is coordinated, and the role of leukocytes in this process, is poorly defined. Recent studies have demonstrated a role for leukocyte-derived epidermal growth factor receptor (EGFR) ligand, amphiregulin, in promoting tissue protection in the intestine and muscle4, 5, and following influenza virus–induced damage in the lung6, 7. The applicant recently illustrated that genetic ablation of amphiregulin in murine regulatory T (Treg) cells results in impaired lung function and markedly reduced airway epithelial repair after challenge with influenza virus in vivo6. Transcriptional profiling and flow cytometric analyses of murine lung Treg cells isolated at 5 days post-infection indicated that these cells express receptors for two hallmark tissue damage cytokines, IL-18 and IL-33, and in vitro treatment of purified naïve Treg cells with either of these cytokines was sufficient to induce amphiregulin production. These findings uncovered an important and previously unknown role for Treg cell–derived amphiregulin in maintaining epithelial barrier integrity during the immune response to a respiratory pathogen. This K22 proposal builds on the applicant's prior study and examines (1) the mechanism by which Treg cell–derived amphiregulin contributes to tissue repair and (2) the role of other amphiregulin-producing leukocytes and tissue-protective mediators in coordinating repair processes throughout the course of influenza infection. Characterizing the molecular and cellular pathways that protect against infectious damage and prevent associated immunopathology will broaden our knowledge of immunological responses and aid in the development of novel therapeutics for treating infectious, allergic, and autoimmune diseases.