Sprouty-Related Ena/Vasodilator-Stimulated Phosphoprotein Homology 1-Domain-Containing Protein-2 Critically Regulates Influenza A Virus-Induced Pneumonia.
Sprouty-Related Ena/Vasodilator-Stimulated Phosphoprotein Homology 1-Domain-Containing Protein-2 Critically Regulates Influenza A Virus-Induced Pneumonia.
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DOI：
10.1097/ccm.0000000000001562
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发表时间：
2016-07
影响因子：
8.8
通讯作者：
Matsukawa A
中科院分区：
文献类型：
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作者：
Ito T;Itakura J;Takahashi S;Sato M;Mino M;Fushimi S;Yamada M;Morishima T;Kunkel SL;Matsukawa A
甲型流感病毒引起急性呼吸道感染，引起年度流行病和偶尔的大流行。虽然许多研究表明，病毒诱导的细胞内信号传导事件在对抗流感病毒感染中是重要的，但特定分子如何在各种细胞内信号传导事件中发挥关键作用的机制尚不清楚。Raf/MEK/ERK级联反应是流感病毒感染过程中的关键信号通路之一，Sprouty相关的Ena/VASP同源1-domain containing protein（Spred）最近被鉴定为Raf依赖的ERK激活的负调节因子。在这里，我们研究了Raf/MEK/ERK级联通过Spred在甲型H1N1流感病毒感染中的作用，因为Spred-2的表达在人流感病毒诱导的肺炎尸检样本中显著增强。前瞻性动物试验。通过鼻内接种H1N1（A/PR/8）感染接种H1N1 WT或Spred-2 KO小鼠的研究实验室野生型（WT）和Spred-2敲除（KO）小鼠。将等体积的PBS鼻内接种到模拟感染的小鼠中。与WT小鼠相比，Spred-2 KO小鼠的H1N1感染导致更高的死亡率，具有更大的病毒载量、过度炎症和增强的细胞因子产生。MEK抑制剂U 0126的施用改善了死亡率并降低了病毒载量和细胞因子水平。此外，骨髓嵌合体表明，H1N1引起的肺部病理是最严重的Spred-2表达缺乏非免疫细胞群体。此外，微阵列分析显示，Spred-2的敲低导致增强的磷脂酰肌醇3-激酶（PI 3 K）信号通路，导致病毒清除由Spred-2表达通过PI 3 K信号通路在小鼠肺上皮细胞中调节。这些数据支持Spred-2在控制流感病毒诱导的肺炎和病毒复制中的重要功能。Spred-2可能是一个新的治疗靶点，用于控制针对H1N1流感病毒感染的免疫应答。
Influenza A virus causes acute respiratory infections that induce annual epidemics and occasional pandemics. While a number of studies indicated that the virus-induced intracellular signaling events are important in combating influenza virus infection, the mechanism how specific molecule plays a critical role among various intracellular signaling events remains unknown. Raf/MEK/ERK cascade is one of the key signaling pathways during influenza virus infection, and the Sprouty-related Ena/VASP homology 1-domain-containing protein (Spred) has recently been identified as a negative regulator of Raf-dependent ERK activation. Here we examined the role of Raf/MEK/ERK cascade through Spred in influenza A (H1N1) viral infection, because the expression of Spred-2 was significantly enhanced in human influenza viral-induced pneumonia autopsy samples. Prospective animal trial. Research laboratory Wild-type (WT) and Spred-2 knockout (KO) mice inoculated with H1N1 WT or Spred-2 KO mice were infected by intranasal inoculation of H1N1(A/PR/8). An equal volume of PBS was inoculated intranasally into mock-infected mice. H1N1 infection of Spred-2 KO mice led to higher mortality with greater viral load, excessive inflammation, and enhanced cytokine production compared with WT mice. Administration of MEK-inhibitor, U0126, improved mortality and reduced both viral load and cytokine levels. Moreover, bone marrow chimeras indicated that H1N1-induced lung pathology was most severe when Spred-2 expression was lacking in nonimmune cell populations. Furthermore, microarray analysis revealed knockdown of Spred-2 led to enhanced phosphatidylinositol 3-kinase (PI3K) signaling pathway, resulting that viral clearance was regulated by Spred-2 expression through the PI3K signaling pathway in murine lung epithelial cells. These data support an important function of Spred-2 in controlling influenza virus-induced pneumonia and viral replication. Spred-2 may be a novel therapeutic target for controlling the immune response against influenza H1N1 virus infection.