JAK-STAT signaling pathways are activated in the brain following reovirus infection
JAK-STAT signaling pathways are activated in the brain following reovirus infection
复制标题
DOI：
10.1080/13550280701344983
复制
发表时间：
2007-08-01
影响因子：
3.2
通讯作者：
Tyler, Kenneth L.
中科院分区：
文献类型：
--
作者：
Goody, Robin J.;Beckham, J. David;Tyler, Kenneth L.
呼肠孤病毒感染为研究中枢神经系统（CNS）病毒感染的发病机制提供了经典的实验模型系统，其中细胞凋亡是细胞死亡的主要机制。作者研究了信号转导子和转录激活子 (STAT)1 的作用，STAT1 是 Janus 激活激酶 (JAK)-STAT 信号传导的一个组成部分，是呼肠孤病毒感染后参与抗病毒反应和调节细胞凋亡的途径。用呼肠孤病毒血清型 3 株 Abney (T3A) 感染原代皮质神经元培养物，导致转录活性关键位点的 STAT1 磷酸化。 T3A 感染后的新生小鼠大脑中也检测到了激活的 STAT1，在病毒引起的损伤区域具有核表达模式。 STAT 蛋白的激活通常由 JAK 介导。作者在 T3A 感染小鼠的脑裂解物中观察到 JAK2 磷酸化 (Tyr 1007/1008)。用抑制剂 AG-490 抑制 JAK 活性可阻断神经元培养物中呼肠孤病毒诱导的 STAT1 激活，表明呼肠孤病毒诱导的 'TAT 激活是 JAK 依赖性的。用抗干扰素 (IFN)-α/β R2 抗体预处理神经元培养物可抑制 T3A 诱导的 STAT1 磷酸化，而 IFN-γ 或 IFN-γ R2 抗体预处理对 T3A 诱导的 STAT1 磷酸化没有任何影响。与野生型动物相比，缺乏 STAT1 基因的小鼠对呼肠孤病毒感染的易感性增加，死亡率增加，大脑中病毒滴度更高。结果表明，呼肠孤病毒感染后，I 型 IFN 介导的、JAK 依赖性 STAT 信号通路被激活，并表明 STAT1 是宿主针对大脑中呼肠孤病毒感染的防御机制的关键组成部分。
Reovirus infection provides a classic experimental model system for studying the pathogenesis of viral infections of the central nervous system (CNS), with apoptosis acting as the major mechanism of cell death. The authors have examined the role of signal transducer and activator of transcription (STAT)1, a component of Janus-activated kinase (JAK)-STAT signaling, a pathway implicated in antiviral responses and pathways regulating apoptosis, following reovirus infection. Infection of primary cortical neuron cultures with reovirus serotype 3 strain Abney (T3A) resulted in phosphorylation of STAT1 at sites critical for transcriptional activity. Activated STAT1 was also detected in the brain of neonatal mice following T3A infection, with a nuclear pattern of expression in areas of virus-induced injury. Activation of STAT proteins is typically mediated by JAKs. The authors observed JAK2 phosphorylation (Tyr 1007/1008) in brain lysates from T3A-infected mice. Inhibition of JAK activity with the inhibitor AG-490 blocked reovirus-induced STAT1 activation in neuronal cultures, indicating reovirus-induced 'TAT activation is JAK dependent. Pretreatment of neuronal cultures with antibody raised against interferon (IFN)-alpha/beta R2 inhibited T3A-induced STAT1 phosphorylation, whereas neither IFN-gamma or IFN-gamma R2 antibody pretreatment had any effect on T3A-induced STAT1 phosphorylation. Mice lacking the STAT1 gene demonstrated increased susceptibility to reovirus infection, with increased mortality and higher viral titers in the brain compared to wild-type animals. The results demonstrate activation of a type I IFN-mediated, JAK-dependent STAT signaling pathway following reovirus infection and suggest that STAT1 is a key component of host defense mechanisms against reovirus infection in the brain.