Regulation and function of innate lymphoid cells during influenza virus infection

说明(申请人提供)：呼吸道病毒感染，包括甲型流感病毒感染的季节性流行，仍然是一个重大的全球公共卫生挑战。成功地从流感病毒感染中恢复需要清除病毒，消除感染引起的炎症，并有效修复受损的肺上皮。虽然多项研究表明获得性免疫在控制病毒复制方面发挥了重要作用， 在感染诱导的损伤后，促进肺上皮细胞修复和重塑的过程仍然缺乏特征。这项建议将询问先天淋巴样细胞(ILCs)在促进甲型流感病毒感染后肺上皮修复方面的影响。在初步研究中，我们确定了一组ILC，这种细胞存在于小鼠和人类的健康肺中。IL-25R、IL-33R和TSLPR在小鼠肺内呈结构性表达，暴露于IL-25、IL-33或TSLP或流感病毒感染后，小鼠肺内ILC的数量显著增加。流感病毒感染后肺内ILCs的耗竭导致肺功能严重下降，呼吸道上皮修复受损，宿主死亡率增加，这表明ILCs作为肺组织内稳态的调节器具有先前未被认识的作用。小鼠肺ILCs的全基因组转录图谱显示，参与伤口愈合和组织修复的基因转录特征强烈丰富，包括表皮生长因子(EGF)家族成员两性调节蛋白。关键的是，给ILC耗竭的小鼠注射双调节素能恢复流感病毒感染小鼠的上皮修复。这些数据提出了一种假设，即靶向肺ILC反应可以在治疗上用于促进包括流感病毒感染在内的多种肺部疾病的修复和缩短恢复时间。利用骨髓嵌合体、选择性体内细胞去除和对IL-25-IL-25R、IL-33-IL-33R、TSLP-TSLPR或EGFR依赖的信号通路的操纵，该项目的两个特定目标将决定(I)上皮细胞衍生细胞因子IL-25、IL-33和TSLP如何调节肺ILC反应；(Ii)ILC衍生的两性调节素和EGFR途径如何促进流感感染后肺上皮修复。总而言之，这些研究将系统地询问ILCs、两用调节素和EGFR信号在促进肺上皮修复中的作用和调节。我们预计，明确肺ILC和双调节蛋白-EGFR通路在肺上皮修复中的作用将指导未来临床努力促进肺上皮屏障功能和组织动态平衡。 在呼吸道多种慢性传染病和炎症性疾病的背景下。

DESCRIPTION (provided by applicant): Respiratory viral infections, including seasonal epidemics of influenza A viral infections, remain a significant global public health challenge. Successful recovery from influenza virus infection requires clearance of the virus, resolution of infection-induced inflammation and effective repair of damaged lung epithelium. While multiple studies have demonstrated an essential role for adaptive immunity in controlling viral replication, the processes that promote repair and remodeling of lung epithelial cells following infection-induced damage remain poorly characterized. This proposal will interrogate the influence of innate lymphoid cells (ILCs) on promoting lung epithelial repair following influenza A virus infection. In preliminary studies, we identified a population of ILCs that is found constitutively n the healthy lung of mice and humans. Lung ILCs in mice constitutively express IL-25R, IL-33R and TSLPR and exhibited a significant population expansion following exposure to IL-25, IL-33 or TSLP or following influenza virus infection. Depletion of lung ILCs following influenza virus infection resulted in severely decreased lung function, impaired airway epithelial repair and increased host mortality, indicating a previously unrecognized role for ILCs as regulators of lung tissue homeostasis. Genome-wide transcriptional profiling of murine lung ILCs revealed a transcriptional signature strongly enriched for genes involved in wound healing and tissue repair including the epidermal growth factor (EGF) family member amphiregulin. Critically, delivery of amphiregulin to ILC-depleted mice restored epithelial repair in influenza virus-infected mice. These data provoke the hypothesis that targeting lung ILC responses could be used therapeutically to promote repair and reduce recovery time in multiple lung diseases including influenza virus infection. Employing bone marrow chimeras, selective in vivo cell depletions and manipulation of the IL-25-IL-25R, IL-33-IL-33R, TSLP-TSLPR or EGFR-dependent signaling pathways, two specific aims of this project will determine (i) how the epithelial cell-derived cytokines IL-25, IL-33 and TSLP regulate lung ILC responses; (ii) how ILC-derived amphiregulin and the EGFR pathway contributes to lung epithelial repair following influenza infection. Collectively, these studies will systematically interrogate the role and regulation of ILCs, amphiregulin and EGFR signaling in promoting lung epithelial repair. We anticipate that defining the contribution of lung ILC and the amphiregulin-EGFR pathway to lung epithelial repair will direct future clinical efforts to promote epithelial barrier function and tissue homeostasis in the context of multiple chronic infectious and inflammatory diseases of the respiratory tract.