Regulation and function of innate lymphoid cells during influenza virus infection

描述（由申请方提供）：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。成功从流感病毒感染中恢复需要清除病毒，解决感染引起的炎症和有效修复受损的肺上皮。虽然多项研究已经证明了适应性免疫在控制病毒复制中的重要作用， 在感染诱导的损伤后促进肺上皮细胞的修复和重塑的过程仍然缺乏表征。该建议将询问先天淋巴样细胞（ILC）对促进甲型流感病毒感染后肺上皮修复的影响。在初步研究中，我们鉴定了在小鼠和人类的健康肺中组成性发现的ILC群体。小鼠中的肺ILC组成型表达IL-25 R、IL-33 R和TSLPR，并且在暴露于IL-25、IL-33或TSLP后或在流感病毒感染后表现出显著的群体扩增。流感病毒感染后肺ILC的耗竭导致肺功能严重下降，气道上皮修复受损和宿主死亡率增加，表明ILC作为肺组织稳态调节剂的作用以前未被认识。小鼠肺ILC的全基因组转录谱显示了转录特征，其强烈富集了参与伤口愈合和组织修复的基因，包括表皮生长因子（EGF）家族成员双调蛋白。重要的是，将双调蛋白递送至ILC缺失的小鼠恢复了流感病毒感染小鼠的上皮修复。这些数据引发了一种假设，即靶向肺ILC反应可以在治疗上用于促进修复并减少包括流感病毒感染在内的多种肺部疾病的恢复时间。本研究的两个具体目标是利用骨髓嵌合体、选择性体内细胞去除和IL-25-IL-25 R、IL-33-IL-33 R、TSLP-TSLPR或EGFR依赖性信号通路的操纵，确定（i）上皮细胞衍生的细胞因子IL-25、IL-33和TSLP如何调节肺ILC反应;（ii）ILC衍生的双调蛋白和EGFR途径如何有助于流感感染后的肺上皮修复。总之，这些研究将系统地探讨ILC、双调蛋白和EGFR信号在促进肺上皮修复中的作用和调节。我们预计，确定肺ILC和双调蛋白-EGFR通路对肺上皮修复的贡献将指导未来的临床努力，以促进肺上皮屏障功能和组织稳态。 呼吸道的多种慢性感染性和炎性疾病的背景下。

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.