A human coronavirus OC43 variant harboring persistence-associated mutations in the S glycoprotein differentially induces the unfolded protein response in human neurons as compared to wild-type virus.
We have reported that human respiratory coronavirus OC43 (HCoV-OC43) is neurotropic and neuroinvasive in humans and mice, and that neurons are the primary target of infection in mice, leading to neurodegenerative disabilities. We now report that an HCoV-OC43 mutant harboring two persistence-associated S glycoprotein point mutations (H183R and Y241H), induced a stronger unfolded protein response (UPR) and translation attenuation in infected human neurons. There was a major contribution of the IRE1/XBP1 pathway, followed by caspase-3 activation and nuclear fragmentation, with no significant role of the ATF6 and eIF2-alpha/ATF4 pathways. Our results show the importance of discrete molecular viral S determinants in virus-neuronal cell interactions that lead to increased production of viral proteins and infectious particles, enhanced UPR activation, and increased cytotoxicity and cell death. As this mutant virus is more neurovirulent in mice, our results also suggest that two mutations in the S glycoprotein could eventually modulate viral neuropathogenesis.
Favreau
Dominique J
DJ
Laboratory of Neuroimmunovirology, INRS-Institut Armand-Frappier,531 boulevard des Prairies, Laval, Québec, Canada H7V 1B7.
Desforges
Marc
M
St-Jean
Julien R
JR
Talbot
Pierre J
PJ
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003332:Coronaviridae / Q000145:classification* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000276:immunology / Q000821:virology; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D064370:Spike Glycoprotein, Coronavirus; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism; D000071717:X-Box Binding Protein 1
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D000071701:Regulatory Factor X Transcription Factors; D064370:Spike Glycoprotein, Coronavirus; D014157:Transcription Factors; D014759:Viral Envelope Proteins; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D051742:Transcription Factor CHOP; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1