The Role of Runx3 in Host Response to Influenza Virus Infection

甲型流感病毒(IAV)以肺上皮细胞为目标，利用宿主细胞机制进行复制，导致 年度流行病和不同严重程度的大流行中的呼吸系统疾病。流感影响所有年龄段， 导致相当大的发病率和死亡率，并对世界卫生和经济造成巨大损失。 季节性流感导致全球25万至50万人死亡，美国约3.6万人死亡 每年一次。目前的治疗是针对病毒的，因此受到流感快速传播能力的限制。 在危重病人身上往往无效。IAV诱导致病的一个关键方面是 肺上皮细胞死亡和炎症，损害肺功能并导致疾病 发病率和死亡率。因此，已经提出了识别和靶向关键可诱导宿主细胞 调节IAV引起的肺损伤、炎症和病毒复制的因素可能提供一个潜在的解决方案 以对抗未来的流感暴发。我们最近报道了转录因子Runx3，但不是RUNX1和 Runx2，是由IAV感染诱导的病毒RNA，是一种合成的双链RNA(DsRNA)类似物 多聚肌胞苷多胞酸(Poly(I：C))和干扰素-(干扰素-)在正常呼吸道上皮细胞和 证实Runx3在IAV感染诱导的细胞死亡等细胞死亡中起重要作用 DsRNA。此外，我们的新的初步数据表明，在IAV感染的小鼠呼吸道中可以诱导Runx3 和肺泡上皮细胞，是dsRNA受体Toll样蛋白表达的重要介质 受体3(TLR3)，有助于对IAV感染产生有害的宿主炎症反应。最初作为IAV 感染呼吸道上皮并诱导强大的先天免疫反应，我们的新发现促使我们 用呼吸道上皮特异性Runx3基因敲除(KO)的小鼠来验证这样的假设 转录因子Runx3可能是呼吸道上皮细胞致病反应的重要调节因子 对IAV感染和体内流感的疾病进展的影响。两个具体的目标将在这方面受到考验 求婚。AIM-1将产生呼吸道上皮细胞特异性Runx3条件性KO小鼠，并确定其对 RUNX3条件KO对LAV诱导的疾病进展的影响；AIM-2将确定AIM-2的作用和机制 RUNX3在IAV诱导的肺损伤和炎症中的作用该R21方案将揭示呼吸道上皮细胞的特异性 Runx3在宿主对IAV感染的反应和流感疾病进展中的作用这项提议将 也使我们能够评估是否控制了呼吸道上皮腔内的初始致病反应 可以限制整体肺损伤和炎症，这可能导致认识到Runx3的调节 为控制宿主对强毒IAV感染的致病反应提供了一种新的策略。

Influenza A virus (IAV) targets lung epithelial cells and exploits the host cell machinery to replicate, causing respiratory illness in annual epidemics and pandemics of variable severity. Influenza affects all age groups, results in considerable morbidity and mortality, and exacts a formidable toll on world health and economics. Seasonal influenza causes 250,000 to 500,000 deaths worldwide and about 36,000 deaths in United States annually. Current therapies target the virus and are therefore limited by the capacity of influenza to rapidly evolve and are frequently ineffective in critically ill patients. One critical aspect of IAV-induced pathogenesis is lung epithelial cell death and inflammation, which compromises pulmonary function and contributes to disease morbidity and mortality. Hence it has been proposed that identification of and targeting key inducible host cell factors that regulate IAV-induced lung injury, inflammation and viral replication may provide a potential solution to combat future influenza outbreaks. We recently reported that transcription factor Runx3, but not Runx1 and Runx2, was induced by IAV infection, viral RNA, a synthetic double-stranded RNA (dsRNA) analog polyinosinicpolycytidylic acid (poly(I:C)) and interferon- (IFN) in normal human airway epithelial cells and demonstrated that Runx3 played a crucial role in the cell death such as apoptosis induced by IAV infection and dsRNA. Moreover, our new preliminary data indicate that Runx3 can be induced in IAV-infected mouse airway and alveolar epithelial cells in vivo and is an important mediator of the expression of dsRNA receptor Toll-like receptor 3 (TLR3) that contributes to a detrimental host inflammatory response to IAV infection. As IAV initially infects the airway epithelium and induces robust innate immune response, our novel findings prompt us to develop mice with airway epithelium specific knockout (KO) of Runx3 to test the hypothesis that the inducible transcription factor Runx3 may be a novel and crucial regulator of airway epithelial cell pathogenic responses to IAV infection and the disease progression of influenza in vivo. Two specific aims will be tested in this proposal. Aim-1 will generate airway epithelium specific Runx3 conditional KO mice and determine the effect of Runx3 conditional KO on lAV-induced disease progression; Aim-2 will determine the role and mechanism of Runx3 in IAV-induced lung injury and inflammation. This R21 proposal will reveal the airway epithelium specific role of Runx3 in host responses to IAV infection and the disease progression of influenza. This proposal will also enable us to assess if controlling the initial pathogenic response in the airway epithelial compartment could limit the overall lung injury and inflammation, which may lead to recognition that modulation of Runx3 offers a novel strategy to control host pathogenic response to the infection of virulent IAV.