Glutamate Excitotoxicity Is Involved in the Induction of Paralysis in Mice after Infection by a Human Coronavirus with a Single Point Mutation in Its Spike Protein
Glutamate Excitotoxicity Is Involved in the Induction of Paralysis in Mice after Infection by a Human Coronavirus with a Single Point Mutation in Its Spike Protein
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DOI：
10.1128/jvi.05576-11
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发表时间：
2011-12-01
影响因子：
5.4
通讯作者：
Talbot, Pierre J.
中科院分区：
文献类型：
--
作者：
Brison, Elodie;Jacomy, Helene;Talbot, Pierre J.
人类冠状病毒（HCoV）是公认的呼吸道病原体，一些菌株（包括 HCoV-OC43）可以感染人类中枢神经系统（CNS）的神经元和神经胶质细胞并激活神经炎症机制。此外，HCoV-OC43 在易感小鼠中具有神经侵袭性、嗜神经性和神经毒性，可诱发慢性脑炎。在此，我们发现病毒刺突（S）糖蛋白（Y241H）的单点突变（在病毒在人类神经细胞中持续存在期间获得）导致受感染小鼠的后肢麻痹性疾病。使用 2-氨基-3-(5-甲基-3-氧代-1,2-恶唑4-基)丙酸 (AMPA) 受体拮抗剂 (GYKI-52466) 抑制谷氨酸兴奋性毒性，改善了 S 突变病毒感染小鼠与瘫痪和运动障碍相关的临床评分，并保护中枢神经系统免受神经元功能障碍，如神经丝磷酸化状态的恢复所示。负责谷氨酸稳态的神经胶质谷氨酸转运蛋白 GLT-1 的表达在感染后下调，而 GYKI-52466 也显着恢复了其稳态表达水平。最后，GYKI-52466 治疗 S 突变病毒感染的小鼠导致小胶质细胞活化减少，这可能会改善 CNS 谷氨酸稳态的调节。综上所述，我们的结果强烈表明，HCoV-OC43 突变体诱发的麻痹相关神经病理学中存在兴奋性毒性，该突变体在其刺突蛋白中存在单点突变，该突变是在持续病毒感染后获得的。
Human coronaviruses (HCoV) are recognized respiratory pathogens, and some strains, including HCoV-OC43, can infect human neuronal and glial cells of the central nervous system (CNS) and activate neuroinflammatory mechanisms. Moreover, HCoV-OC43 is neuroinvasive, neurotropic, and neurovirulent in susceptible mice, where it induces chronic encephalitis. Herein, we show that a single point mutation in the viral spike (S) glycoprotein (Y241H), acquired during viral persistence in human neural cells, led to a hind-limb paralytic disease in infected mice. Inhibition of glutamate excitotoxicity using a 2-amino-3-(5-methyl-3-oxo-1,2-oxazol4-yl) propranoic acid (AMPA) receptor antagonist (GYKI-52466) improved clinical scores related to the paralysis and motor disabilities in S mutant virus-infected mice, as well as protected the CNS from neuronal dysfunctions, as illustrated by restoration of the phosphorylation state of neurofilaments. Expression of the glial glutamate transporter GLT-1, responsible for glutamate homeostasis, was downregulated following infection, and GYKI-52466 also significantly restored its steady-state expression level. Finally, GYKI-52466 treatment of S mutant virus-infected mice led to reduced microglial activation, which may lead to improvement in the regulation of CNS glutamate homeostasis. Taken together, our results strongly suggest an involvement of excitotoxicity in the paralysis-associated neuropathology induced by an HCoV-OC43 mutant which harbors a single point mutation in its spike protein that is acquired upon persistent virus infection.