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Cleavage of a Neuroinvasive Human Respiratory Virus Spike Glycoprotein by Proprotein Convertases Modulates Neurovirulence and Virus Spread within the Central Nervous System.
PLoS Pathog. 2015; 11(11):e1005261.PP

Abstract

Human coronaviruses (HCoV) are respiratory pathogens that may be associated with the development of neurological diseases, in view of their neuroinvasive and neurotropic properties. The viral spike (S) glycoprotein is a major virulence factor for several coronavirus species, including the OC43 strain of HCoV (HCoV-OC43). In an attempt to study the role of this protein in virus spread within the central nervous system (CNS) and neurovirulence, as well as to identify amino acid residues important for such functions, we compared the sequence of the S gene found in the laboratory reference strain HCoV-OC43 ATCC VR-759 to S sequences of viruses detected in clinical isolates from the human respiratory tract. We identified one predominant mutation at amino acid 758 (from RRSR↓ G758 to RRSR↓R758), which introduces a putative furin-like cleavage (↓) site. Using a molecular cDNA infectious clone to generate a corresponding recombinant virus, we show for the first time that such point mutation in the HCoV-OC43 S glycoprotein creates a functional cleavage site between the S1 and S2 portions of the S protein. While the corresponding recombinant virus retained its neuroinvasive properties, this mutation led to decreased neurovirulence while potentially modifying the mode of virus spread, likely leading to a limited dissemination within the CNS. Taken together, these results are consistent with the adaptation of HCoV-OC43 to the CNS environment, resulting from the selection of quasi-species harboring mutations that lead to amino acid changes in viral genes, like the S gene in HCoV-OC43, which may contribute to a more efficient establishment of a less pathogenic but persistent CNS infection. This adaptative mechanism could potentially be associated with human encephalitis or other neurological degenerative pathologies.

Authors+Show Affiliations

Laboratory of Neuroimmunovirology, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada.Laboratory of Neuroimmunovirology, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada.Laboratory of Neuroimmunovirology, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada.Laboratory of Neuroimmunovirology, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada.Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montréal, Québec, Canada.Laboratory of Neuroimmunovirology, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26545254

Citation

Le Coupanec, Alain, et al. "Cleavage of a Neuroinvasive Human Respiratory Virus Spike Glycoprotein By Proprotein Convertases Modulates Neurovirulence and Virus Spread Within the Central Nervous System." PLoS Pathogens, vol. 11, no. 11, 2015, pp. e1005261.
Le Coupanec A, Desforges M, Meessen-Pinard M, et al. Cleavage of a Neuroinvasive Human Respiratory Virus Spike Glycoprotein by Proprotein Convertases Modulates Neurovirulence and Virus Spread within the Central Nervous System. PLoS Pathog. 2015;11(11):e1005261.
Le Coupanec, A., Desforges, M., Meessen-Pinard, M., Dubé, M., Day, R., Seidah, N. G., & Talbot, P. J. (2015). Cleavage of a Neuroinvasive Human Respiratory Virus Spike Glycoprotein by Proprotein Convertases Modulates Neurovirulence and Virus Spread within the Central Nervous System. PLoS Pathogens, 11(11), e1005261. https://doi.org/10.1371/journal.ppat.1005261
Le Coupanec A, et al. Cleavage of a Neuroinvasive Human Respiratory Virus Spike Glycoprotein By Proprotein Convertases Modulates Neurovirulence and Virus Spread Within the Central Nervous System. PLoS Pathog. 2015;11(11):e1005261. PubMed PMID: 26545254.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cleavage of a Neuroinvasive Human Respiratory Virus Spike Glycoprotein by Proprotein Convertases Modulates Neurovirulence and Virus Spread within the Central Nervous System. AU - Le Coupanec,Alain, AU - Desforges,Marc, AU - Meessen-Pinard,Mathieu, AU - Dubé,Mathieu, AU - Day,Robert, AU - Seidah,Nabil G, AU - Talbot,Pierre J, Y1 - 2015/11/06/ PY - 2015/07/23/received PY - 2015/10/16/accepted PY - 2015/11/7/entrez PY - 2015/11/7/pubmed PY - 2016/4/14/medline SP - e1005261 EP - e1005261 JF - PLoS pathogens JO - PLoS Pathog VL - 11 IS - 11 N2 - Human coronaviruses (HCoV) are respiratory pathogens that may be associated with the development of neurological diseases, in view of their neuroinvasive and neurotropic properties. The viral spike (S) glycoprotein is a major virulence factor for several coronavirus species, including the OC43 strain of HCoV (HCoV-OC43). In an attempt to study the role of this protein in virus spread within the central nervous system (CNS) and neurovirulence, as well as to identify amino acid residues important for such functions, we compared the sequence of the S gene found in the laboratory reference strain HCoV-OC43 ATCC VR-759 to S sequences of viruses detected in clinical isolates from the human respiratory tract. We identified one predominant mutation at amino acid 758 (from RRSR↓ G758 to RRSR↓R758), which introduces a putative furin-like cleavage (↓) site. Using a molecular cDNA infectious clone to generate a corresponding recombinant virus, we show for the first time that such point mutation in the HCoV-OC43 S glycoprotein creates a functional cleavage site between the S1 and S2 portions of the S protein. While the corresponding recombinant virus retained its neuroinvasive properties, this mutation led to decreased neurovirulence while potentially modifying the mode of virus spread, likely leading to a limited dissemination within the CNS. Taken together, these results are consistent with the adaptation of HCoV-OC43 to the CNS environment, resulting from the selection of quasi-species harboring mutations that lead to amino acid changes in viral genes, like the S gene in HCoV-OC43, which may contribute to a more efficient establishment of a less pathogenic but persistent CNS infection. This adaptative mechanism could potentially be associated with human encephalitis or other neurological degenerative pathologies. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/26545254/Cleavage_of_a_Neuroinvasive_Human_Respiratory_Virus_Spike_Glycoprotein_by_Proprotein_Convertases_Modulates_Neurovirulence_and_Virus_Spread_within_the_Central_Nervous_System_ L2 - https://dx.plos.org/10.1371/journal.ppat.1005261 DB - PRIME DP - Unbound Medicine ER -