Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication

Abstract Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract disease in infants, young children, the elderly and immunocompromised individuals. Therapy for RSV infections is limited to high risk infants and there are no safe and efficacious vaccines. Matrix (M)...

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Autores principales:	Cynthia Mathew, Sharon Tamir, Ralph A. Tripp, Reena Ghildyal
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/010a40d4f4ac4e098a1bb5e948447db9
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spelling	oai:doaj.org-article:010a40d4f4ac4e098a1bb5e948447db92021-12-02T17:17:40ZReversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication10.1038/s41598-021-98767-22045-2322https://doaj.org/article/010a40d4f4ac4e098a1bb5e948447db92021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98767-2https://doaj.org/toc/2045-2322Abstract Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract disease in infants, young children, the elderly and immunocompromised individuals. Therapy for RSV infections is limited to high risk infants and there are no safe and efficacious vaccines. Matrix (M) protein is a major RSV structural protein with a key role in virus assembly. Interestingly, M is localised to the nucleus early in infection and its export into the cytoplasm by the nuclear exporter, exportin-1 (XPO1) is essential for RSV assembly. We have shown previously that chemical inhibition of XPO1 function results in reduced RSV replication. In this study, we have investigated the anti-RSV efficacy of Selective Inhibitor of Nuclear Export (SINE) compounds, KPT-335 and KPT-185. Our data shows that therapeutic administration of the SINE compounds results in reduced RSV titre in human respiratory epithelial cell culture. Within 24 h of treatment, RSV replication and XPO1 expression was reduced, M protein was partially retained in the nucleus, and cell cycle progression was delayed. Notably, the effect of SINE compounds was reversible within 24 h after their removal. Our data show that reversible inhibition of XPO1 can disrupt RSV replication by affecting downstream pathways regulated by the nuclear exporter.Cynthia MathewSharon TamirRalph A. TrippReena GhildyalNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cynthia Mathew Sharon Tamir Ralph A. Tripp Reena Ghildyal Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication
description	Abstract Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract disease in infants, young children, the elderly and immunocompromised individuals. Therapy for RSV infections is limited to high risk infants and there are no safe and efficacious vaccines. Matrix (M) protein is a major RSV structural protein with a key role in virus assembly. Interestingly, M is localised to the nucleus early in infection and its export into the cytoplasm by the nuclear exporter, exportin-1 (XPO1) is essential for RSV assembly. We have shown previously that chemical inhibition of XPO1 function results in reduced RSV replication. In this study, we have investigated the anti-RSV efficacy of Selective Inhibitor of Nuclear Export (SINE) compounds, KPT-335 and KPT-185. Our data shows that therapeutic administration of the SINE compounds results in reduced RSV titre in human respiratory epithelial cell culture. Within 24 h of treatment, RSV replication and XPO1 expression was reduced, M protein was partially retained in the nucleus, and cell cycle progression was delayed. Notably, the effect of SINE compounds was reversible within 24 h after their removal. Our data show that reversible inhibition of XPO1 can disrupt RSV replication by affecting downstream pathways regulated by the nuclear exporter.
format	article
author	Cynthia Mathew Sharon Tamir Ralph A. Tripp Reena Ghildyal
author_facet	Cynthia Mathew Sharon Tamir Ralph A. Tripp Reena Ghildyal
author_sort	Cynthia Mathew
title	Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication
title_short	Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication
title_full	Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication
title_fullStr	Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication
title_full_unstemmed	Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication
title_sort	reversible disruption of xpo1-mediated nuclear export inhibits respiratory syncytial virus (rsv) replication
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/010a40d4f4ac4e098a1bb5e948447db9
work_keys_str_mv	AT cynthiamathew reversibledisruptionofxpo1mediatednuclearexportinhibitsrespiratorysyncytialvirusrsvreplication AT sharontamir reversibledisruptionofxpo1mediatednuclearexportinhibitsrespiratorysyncytialvirusrsvreplication AT ralphatripp reversibledisruptionofxpo1mediatednuclearexportinhibitsrespiratorysyncytialvirusrsvreplication AT reenaghildyal reversibledisruptionofxpo1mediatednuclearexportinhibitsrespiratorysyncytialvirusrsvreplication
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Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication

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