Goody Robin J, Beckham J David, Rubtsova Kira, Tyler Kenneth L
Departments of Neurology, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA.
J Neurovirol. 2007 Aug;13(4):373-83. doi: 10.1080/13550280701344983.
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 STAT activation is JAK dependent. Pretreatment of neuronal cultures with antibody raised against interferon (IFN)-alpha/betaR2 inhibited T3A-induced STAT1 phosphorylation, whereas neither IFN-gamma or IFN-gammaR2 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.
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一个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信号通路的一个组成部分，该通路与抗病毒反应以及调节细胞凋亡的通路有关，在呼肠孤病毒感染后发挥作用。用呼肠孤病毒3型Abney株（T3A）感染原代皮质神经元培养物，导致STAT1在对转录活性至关重要的位点发生磷酸化。在T3A感染后的新生小鼠大脑中也检测到了活化的STAT1，在病毒诱导损伤区域呈核表达模式。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（酪氨酸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STAT激活依赖于JAK。用抗干扰素（IFN）-α/βR2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-γR2抗体预处理对T3A诱导的STAT1磷酸化均无影响。缺乏STAT1基因的小鼠对呼肠孤病毒感染的易感性增加，与野生型动物相比，死亡率增加且脑中病毒滴度更高。结果表明呼肠孤病毒感染后I型干扰素介导的、依赖JAK的STAT信号通路被激活，提示STAT1是大脑中宿主防御呼肠孤病毒感染机制的关键组成部分。
