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Potential differences in cleavage of the S protein and type-1 interferon together control human coronavirus infection, propagation, and neuropathology within the central nervous system.
J Virol. 2021 Feb 24 [Online ahead of print]JV

Abstract

Human coronaviruses (HCoV) are respiratory pathogens which have been known since the 1960's. In December 2019, a new betacoronavirus, SARS-CoV-2, was reported and is responsible for one of the biggest pandemics of the last two centuries. Similar to the HCoV-OC43 strain, available evidence suggests SARS-CoV-2 neuroinvasion associated with potential neurological disorders. Coronavirus infection of the central nervous system (CNS) is largely controlled by a viral factor, the spike glycoprotein (S) and a host factor, innate immunity. However, the interaction between these two factors remains elusive. Proteolytic cleavage of the S protein can occur at the interface between receptor binding (S1) and fusion (S2) domains (S1/S2), as well as in a position adjacent to a fusion peptide within S2 (S2'). Herein, using HCoV-OC43 as a surrogate for SARS-CoV-2, we report that both S protein sites are involved in neurovirulence and are required for optimal CNS infection. Whereas efficient cleavage at S1/S2 is associated with decreased virulence, the potentially cleavable putative S2' site is essential for efficient viral infection. Furthermore, type 1 interferon (IFN 1)-related innate immunity also plays an important role in the control of viral spread towards the spinal cord, by preventing infection of ependymal cells. Our results underline the link between the differential S cleavage and IFN 1 in the prevention of viral spread, to control the severity of infection and pathology in both immunocompetent and immunodeficient mice. Taken together, these results point towards two potential therapeutic anti-viral targets: cleavage of the S protein in conjunction with efficient IFN 1-related innate immunity to prevent or at least reduce neuroinvasion, neural spread, and potential associated neurovirulence of human coronaviruses.ImportanceHuman coronaviruses (HCoV) are recognized respiratory pathogens. The emergence of the novel pathogenic member of this family in December 2019 (SARS-CoV-2, which causes COVID-19) poses a global health emergency. As with other coronaviruses reported previously, invasion of the human central nervous system (CNS), associated with diverse neurological disorders, was suggested for SARS-CoV-2. Herein, using the related HCoV-OC43 strain, we show that the viral spike protein constitutes a major neurovirulence factor and that type 1 interferon (IFN 1), in conjunction with cleavage of S protein by host proteases, represent important host factors that participate in the control of CNS infection.To our knowledge, this is the first demonstration of a direct link between cleavage of the S protein, innate immunity and neurovirulence. Understanding mechanisms of viral infection and spread in neuronal cells is essential to better design therapeutic strategies, and to prevent infection by human coronaviruses such as SARS-CoV-2 in human CNS especially in the vulnerable populations such as the elderly and immune-compromised individuals.

Authors+Show Affiliations

Laboratory of Neuroimmunovirology, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada H7V 1B7.Laboratory of Neuroimmunovirology, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada H7V 1B7 pierre.talbot@iaf.inrs.ca marc.desforges.hsj@ssss.gouv.qc.ca. Laboratory of microbiology, CHU Ste-Justine, Montreal, Québec, Canada, H3T 1C5.Fachbereich Veterinärmedizin, Institut für virologie, Robert Von Ostertag-Str. 7 - 134163 Berlin.Laboratory of Neuroimmunovirology, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada H7V 1B7.Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada K1H 8M5. Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada K1H 8M5.Laboratory of Neuroimmunovirology, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada H7V 1B7 pierre.talbot@iaf.inrs.ca marc.desforges.hsj@ssss.gouv.qc.ca.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33627397

Citation

Le Coupanec, Alain, et al. "Potential Differences in Cleavage of the S Protein and Type-1 Interferon Together Control Human Coronavirus Infection, Propagation, and Neuropathology Within the Central Nervous System." Journal of Virology, 2021.
Le Coupanec A, Desforges M, Kaufer B, et al. Potential differences in cleavage of the S protein and type-1 interferon together control human coronavirus infection, propagation, and neuropathology within the central nervous system. J Virol. 2021.
Le Coupanec, A., Desforges, M., Kaufer, B., Dubeau, P., Côté, M., & Talbot, P. J. (2021). Potential differences in cleavage of the S protein and type-1 interferon together control human coronavirus infection, propagation, and neuropathology within the central nervous system. Journal of Virology. https://doi.org/10.1128/JVI.00140-21
Le Coupanec A, et al. Potential Differences in Cleavage of the S Protein and Type-1 Interferon Together Control Human Coronavirus Infection, Propagation, and Neuropathology Within the Central Nervous System. J Virol. 2021 Feb 24; PubMed PMID: 33627397.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Potential differences in cleavage of the S protein and type-1 interferon together control human coronavirus infection, propagation, and neuropathology within the central nervous system. AU - Le Coupanec,Alain, AU - Desforges,Marc, AU - Kaufer,Benedikt, AU - Dubeau,Philippe, AU - Côté,Marceline, AU - Talbot,Pierre J, Y1 - 2021/02/24/ PY - 2021/2/25/entrez PY - 2021/2/26/pubmed PY - 2021/2/26/medline JF - Journal of virology JO - J Virol N2 - Human coronaviruses (HCoV) are respiratory pathogens which have been known since the 1960's. In December 2019, a new betacoronavirus, SARS-CoV-2, was reported and is responsible for one of the biggest pandemics of the last two centuries. Similar to the HCoV-OC43 strain, available evidence suggests SARS-CoV-2 neuroinvasion associated with potential neurological disorders. Coronavirus infection of the central nervous system (CNS) is largely controlled by a viral factor, the spike glycoprotein (S) and a host factor, innate immunity. However, the interaction between these two factors remains elusive. Proteolytic cleavage of the S protein can occur at the interface between receptor binding (S1) and fusion (S2) domains (S1/S2), as well as in a position adjacent to a fusion peptide within S2 (S2'). Herein, using HCoV-OC43 as a surrogate for SARS-CoV-2, we report that both S protein sites are involved in neurovirulence and are required for optimal CNS infection. Whereas efficient cleavage at S1/S2 is associated with decreased virulence, the potentially cleavable putative S2' site is essential for efficient viral infection. Furthermore, type 1 interferon (IFN 1)-related innate immunity also plays an important role in the control of viral spread towards the spinal cord, by preventing infection of ependymal cells. Our results underline the link between the differential S cleavage and IFN 1 in the prevention of viral spread, to control the severity of infection and pathology in both immunocompetent and immunodeficient mice. Taken together, these results point towards two potential therapeutic anti-viral targets: cleavage of the S protein in conjunction with efficient IFN 1-related innate immunity to prevent or at least reduce neuroinvasion, neural spread, and potential associated neurovirulence of human coronaviruses.ImportanceHuman coronaviruses (HCoV) are recognized respiratory pathogens. The emergence of the novel pathogenic member of this family in December 2019 (SARS-CoV-2, which causes COVID-19) poses a global health emergency. As with other coronaviruses reported previously, invasion of the human central nervous system (CNS), associated with diverse neurological disorders, was suggested for SARS-CoV-2. Herein, using the related HCoV-OC43 strain, we show that the viral spike protein constitutes a major neurovirulence factor and that type 1 interferon (IFN 1), in conjunction with cleavage of S protein by host proteases, represent important host factors that participate in the control of CNS infection.To our knowledge, this is the first demonstration of a direct link between cleavage of the S protein, innate immunity and neurovirulence. Understanding mechanisms of viral infection and spread in neuronal cells is essential to better design therapeutic strategies, and to prevent infection by human coronaviruses such as SARS-CoV-2 in human CNS especially in the vulnerable populations such as the elderly and immune-compromised individuals. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/33627397/Potential_differences_in_cleavage_of_the_S_protein_and_type_1_interferon_together_control_human_coronavirus_infection_propagation_and_neuropathology_within_the_central_nervous_system_ L2 - https://journals.asm.org/doi/10.1128/JVI.00140-21?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -
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