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Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors.
J Gen Virol. 2018 05; 99(5):619-630.JG

Abstract

Enveloped viruses gain entry into host cells by fusing with cellular membranes, a step that is required for virus replication. Coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and infectious bronchitis virus (IBV), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes, depending on the cell or tissue type. The virus spike (S) protein mediates fusion with the host cell membrane. We have shown previously that an Abelson (Abl) kinase inhibitor, imatinib, significantly reduces SARS-CoV and MERS-CoV viral titres and prevents endosomal entry by HIV SARS S and MERS S pseudotyped virions. SARS-CoV and MERS-CoV are classified as BSL-3 viruses, which makes experimentation into the cellular mechanisms involved in infection more challenging. Here, we use IBV, a BSL-2 virus, as a model for studying the role of Abl kinase activity during coronavirus infection. We found that imatinib and two specific Abl kinase inhibitors, GNF2 and GNF5, reduce IBV titres by blocking the first round of virus infection. Additionally, all three drugs prevented IBV S-induced syncytia formation prior to the hemifusion step. Our results indicate that membrane fusion (both virus-cell and cell-cell) is blocked in the presence of Abl kinase inhibitors. Studying the effects of Abl kinase inhibitors on IBV will be useful in identifying the host cell pathways required for coronavirus infection. This will provide an insight into possible therapeutic targets to treat infections by current as well as newly emerging coronaviruses.

Authors+Show Affiliations

Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

29557770

Citation

Sisk, Jeanne M., et al. "Coronavirus S Protein-induced Fusion Is Blocked Prior to Hemifusion By Abl Kinase Inhibitors." The Journal of General Virology, vol. 99, no. 5, 2018, pp. 619-630.
Sisk JM, Frieman MB, Machamer CE. Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors. J Gen Virol. 2018;99(5):619-630.
Sisk, J. M., Frieman, M. B., & Machamer, C. E. (2018). Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors. The Journal of General Virology, 99(5), 619-630. https://doi.org/10.1099/jgv.0.001047
Sisk JM, Frieman MB, Machamer CE. Coronavirus S Protein-induced Fusion Is Blocked Prior to Hemifusion By Abl Kinase Inhibitors. J Gen Virol. 2018;99(5):619-630. PubMed PMID: 29557770.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors. AU - Sisk,Jeanne M, AU - Frieman,Matthew B, AU - Machamer,Carolyn E, Y1 - 2018/03/20/ PY - 2018/3/21/pubmed PY - 2019/3/28/medline PY - 2018/3/21/entrez KW - Abl kinase KW - Abl1 KW - Abl2 KW - GNF2 KW - GNF5 KW - IBV KW - MERS-CoV KW - SARS-CoV KW - cell-cell fusion KW - coronavirus KW - imatinib KW - virus-cell fusion SP - 619 EP - 630 JF - The Journal of general virology JO - J. Gen. Virol. VL - 99 IS - 5 N2 - Enveloped viruses gain entry into host cells by fusing with cellular membranes, a step that is required for virus replication. Coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and infectious bronchitis virus (IBV), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes, depending on the cell or tissue type. The virus spike (S) protein mediates fusion with the host cell membrane. We have shown previously that an Abelson (Abl) kinase inhibitor, imatinib, significantly reduces SARS-CoV and MERS-CoV viral titres and prevents endosomal entry by HIV SARS S and MERS S pseudotyped virions. SARS-CoV and MERS-CoV are classified as BSL-3 viruses, which makes experimentation into the cellular mechanisms involved in infection more challenging. Here, we use IBV, a BSL-2 virus, as a model for studying the role of Abl kinase activity during coronavirus infection. We found that imatinib and two specific Abl kinase inhibitors, GNF2 and GNF5, reduce IBV titres by blocking the first round of virus infection. Additionally, all three drugs prevented IBV S-induced syncytia formation prior to the hemifusion step. Our results indicate that membrane fusion (both virus-cell and cell-cell) is blocked in the presence of Abl kinase inhibitors. Studying the effects of Abl kinase inhibitors on IBV will be useful in identifying the host cell pathways required for coronavirus infection. This will provide an insight into possible therapeutic targets to treat infections by current as well as newly emerging coronaviruses. SN - 1465-2099 UR - https://www.unboundmedicine.com/medline/citation/29557770/Coronavirus_S_protein_induced_fusion_is_blocked_prior_to_hemifusion_by_Abl_kinase_inhibitors_ L2 - http://jgv.microbiologyresearch.org/pubmed/content/journal/jgv/10.1099/jgv.0.001047 DB - PRIME DP - Unbound Medicine ER -