title: 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.
abstract: 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-oxazol-4-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.
authors.affiliation: Laboratory of Neuroimmunovirology, INRS-Institut Armand Frappier, 513 boulevard des Prairies, Laval, Québec, Canada H7V 1B7.
authors.forename: Elodie
authors.initials: E
authors.lastname: Brison
authors.forename: Hélène
authors.initials: H
authors.lastname: Jacomy
authors.forename: Marc
authors.initials: M
authors.lastname: Desforges
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Talbot
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage; D015153:Blotting, Western; D018352:Coronavirus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D028962:Coronavirus OC43, Human / Q000235:genetics / Q000472:pathogenicity*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007124:Immunoenzyme Techniques; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology* / Q000821:virology; D009474:Neurons / Q000187:drug effects / Q000473:pathology* / Q000821:virology; D010243:Paralysis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D064370:Spike Glycoprotein, Coronavirus; D015996:Survival Rate; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D008562:Membrane Glycoproteins; D018091:Receptors, AMPA; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; C061950:GYKI 52466; D001569:Benzodiazepines; D018698:Glutamic Acid