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. 2010;16(4):279–293. doi: 10.3109/13550284.2010.497806

Mutations in the spike glycoprotein of human coronavirus OC43 modulate disease in BALB/c mice from encephalitis to flaccid paralysis and demyelination

Hélène Jacomy 1, Julien R St-Jean 1, Élodie Brison 1, Gabriel Marceau 1, Marc Desforges 1, Pierre J Talbot 1,✉
PMCID: PMC7095228  PMID: 20642316

Abstract

The etiology of most neurodegenerative diseases of the central nervous system remains unknown and likely involves a combination of genetic susceptibility and environmental triggering factors. Given that exposure to numerous infectious pathogens occurs during childhood, and that some viral infections can lead to neurodegeneration and demyelination, it is conceivable that some viruses may act as triggering factors in neuropathogenesis. We have previously shown that the prototype OC43 strain of the common cold—associated human respiratory coronavirus has the capacity to infect human neuronal and glial cells and does persist in human brains. Moreover, it has neuroinvasive properties in susceptible BALB/c mice, where it leads to a chronic encephalitis with accompanying disabilities. Here, we show that mutations in the viral spike glycoprotein, reproducibly acquired during viral persistence in human neural cell cultures, led to a drastically modified virus-induced neuropathology in BALB/c mice, characterized by flaccid paralysis and demyelination. Even though infection by both mutated and wild-type viruses led to neuroinflammation, the modified neuropathogenesis induced by the mutated virus was associated with increased viral spread and significantly more CD4+ and CD8+ T-lymphocyte infiltration into the central nervous system, as well as significantly increased levels of the proinflammatory cytokine interleukin (IL)-6 and the chemokine CCL2 (monocyte chemoattractant protein [MCP]-1). Moreover, recombinant virus harboring the S glycoprotein mutations retained its neurotropism, productively infecting neurons. Therefore, interaction of a human respiratory coronavirus with the central nervous system may modulate virus and host factors resulting in a modified neuropathogenesis in genetically susceptible individuals.

Keywords: cytokines/chemokines, demyelination, inflammation, mutations, neurological disease, paralysis

Footnotes

This work was supported by grant no. MT-9203 from the Canadian Institutes of Health Research (Institute of Infection and Immunity). Pierre J. Talbot is the holder of the Tier-1 Canada Research Chair in Neuroimmunovirology. Julien R. St-Jean acknowledges a studentship from the Fonds québécois de recherche sur la nature et les technologies (FQRNT).

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