Involvement of the Rabies Virus Phosphoprotein Gene in Neuroinvasiveness
Involvement of the Rabies Virus Phosphoprotein Gene in Neuroinvasiveness
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DOI：
10.1128/jvi.02132-13
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发表时间：
2013-11-01
影响因子：
5.4
通讯作者：
Sugiyama, Makoto
中科院分区：
文献类型：
--
作者：
Yamaoka, Satoko;Ito, Naoto;Sugiyama, Makoto
狂犬病病毒（RABV）通过患狂犬病的动物咬伤传播，感染周围神经，然后扩散到中枢神经系统（CNS），然后在被感染者中引起严重的神经系统症状和死亡。尽管这种病毒从外周部位扩散到中枢神经系统（神经侵袭性）的能力在狂犬病的发病机制中很重要，但对RABV神经侵袭性的机制知之甚少。在本研究中，为了深入了解RABV的作用机制，我们对两种固定RABV菌株Nishigahara和衍生菌株Ni-CE进行了对比分析，这两种固定RABV菌株分别在小鼠肌肉注射后引起致死和无症状感染。在Ni-CE的遗传背景下，对一系列含有Nishigahara基因的嵌合病毒进行了检测，发现Nishigahara磷酸化蛋白(P)基因通过介导周围神经的感染在神经侵袭中起重要作用。体内和体外实验的结果强烈表明，Nishigahara P基因，而不是Ni-CE P基因，对肌肉细胞中病毒的稳定复制起重要作用。在先前RABV磷酸化蛋白抵消宿主干扰素（IFN）系统的基础上，进一步的研究表明Nishigahara P基因，而不是Ni-CE P基因，在肌肉细胞中抑制β干扰素（IFN- β）基因（IFN- β）和IFN刺激基因的表达。总之，我们提供了第一个强有力的数据，表明RABV磷蛋白通过对抗宿主IFN系统来协助病毒在肌肉细胞中的复制，从而增强周围神经的感染。
Rabies virus (RABV), which is transmitted via a bite wound caused by a rabid animal, infects peripheral nerves and then spreads to the central nervous system (CNS) before causing severe neurological symptoms and death in the infected individual. Despite the importance of this ability of the virus to spread from a peripheral site to the CNS (neuroinvasiveness) in the pathogenesis of rabies, little is known about the mechanism underlying the neuroinvasiveness of RABV. In this study, to obtain insights into the mechanism, we conducted comparative analysis of two fixed RABV strains, Nishigahara and the derivative strain Ni-CE, which cause lethal and asymptomatic infections, respectively, in mice after intramuscular inoculation. Examination of a series of chimeric viruses harboring the respective genes from Nishigahara in the genetic background of Ni-CE revealed that the Nishigahara phosphoprotein (P) gene plays a major role in the neuroinvasiveness by mediating infection of peripheral nerves. The results obtained from both in vivo and in vitro experiments strongly suggested that the Nishigahara P gene, but not the Ni-CE P gene, is important for stable viral replication in muscle cells. Further investigation based on the previous finding that RABV phosphoprotein counteracts the host interferon (IFN) system demonstrated that the Nishigahara P gene, but not the Ni-CE P gene, functions to suppress expression of the beta interferon (IFN-beta) gene (Ifn-beta) and IFN-stimulated genes in muscle cells. In conclusion, we provide the first data strongly suggesting that RABV phosphoprotein assists viral replication in muscle cells by counteracting the host IFN system and, consequently, enhances infection of peripheral nerves.