Coronaviruses Induce Entry-Independent, Continuous Macropinocytosis

ABSTRACT Macropinocytosis is exploited by many pathogens for entry into cells. Coronaviruses (CoVs) such as severe acute respiratory syndrome (SARS) CoV and Middle East respiratory syndrome CoV are important human pathogens; however, macropinocytosis during CoV infection has not been investigated. W...

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Autores principales:	Megan Culler Freeman, Christopher T. Peek, Michelle M. Becker, Everett Clinton Smith, Mark R. Denison
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ed2ee7acc73d4ae1857ac8007863e319
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spelling	oai:doaj.org-article:ed2ee7acc73d4ae1857ac8007863e3192021-11-15T15:47:21ZCoronaviruses Induce Entry-Independent, Continuous Macropinocytosis10.1128/mBio.01340-142150-7511https://doaj.org/article/ed2ee7acc73d4ae1857ac8007863e3192014-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01340-14https://doaj.org/toc/2150-7511ABSTRACT Macropinocytosis is exploited by many pathogens for entry into cells. Coronaviruses (CoVs) such as severe acute respiratory syndrome (SARS) CoV and Middle East respiratory syndrome CoV are important human pathogens; however, macropinocytosis during CoV infection has not been investigated. We demonstrate that the CoVs SARS CoV and murine hepatitis virus (MHV) induce macropinocytosis, which occurs late during infection, is continuous, and is not associated with virus entry. MHV-induced macropinocytosis results in vesicle internalization, as well as extended filopodia capable of fusing with distant cells. MHV-induced macropinocytosis requires fusogenic spike protein on the cell surface and is dependent on epidermal growth factor receptor activation. Inhibition of macropinocytosis reduces supernatant viral titers and syncytia but not intracellular virus titers. These results indicate that macropinocytosis likely facilitates CoV infection through enhanced cell-to-cell spreading. Our studies are the first to demonstrate virus use of macropinocytosis for a role other than entry and suggest a much broader potential exploitation of macropinocytosis in virus replication and host interactions. IMPORTANCE Coronaviruses (CoVs), including severe acute respiratory syndrome (SARS) CoV and Middle East respiratory syndrome CoV, are critical emerging human pathogens. Macropinocytosis is induced by many pathogens to enter host cells, but other functions for macropinocytosis in virus replication are unknown. In this work, we show that CoVs induce a macropinocytosis late in infection that is continuous, independent from cell entry, and associated with increased virus titers and cell fusion. Murine hepatitis virus macropinocytosis requires a fusogenic virus spike protein and signals through the epidermal growth factor receptor and the classical macropinocytosis pathway. These studies demonstrate CoV induction of macropinocytosis for a purpose other than entry and indicate that viruses likely exploit macropinocytosis at multiple steps in replication and pathogenesis.Megan Culler FreemanChristopher T. PeekMichelle M. BeckerEverett Clinton SmithMark R. DenisonAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 4 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Megan Culler Freeman Christopher T. Peek Michelle M. Becker Everett Clinton Smith Mark R. Denison Coronaviruses Induce Entry-Independent, Continuous Macropinocytosis
description	ABSTRACT Macropinocytosis is exploited by many pathogens for entry into cells. Coronaviruses (CoVs) such as severe acute respiratory syndrome (SARS) CoV and Middle East respiratory syndrome CoV are important human pathogens; however, macropinocytosis during CoV infection has not been investigated. We demonstrate that the CoVs SARS CoV and murine hepatitis virus (MHV) induce macropinocytosis, which occurs late during infection, is continuous, and is not associated with virus entry. MHV-induced macropinocytosis results in vesicle internalization, as well as extended filopodia capable of fusing with distant cells. MHV-induced macropinocytosis requires fusogenic spike protein on the cell surface and is dependent on epidermal growth factor receptor activation. Inhibition of macropinocytosis reduces supernatant viral titers and syncytia but not intracellular virus titers. These results indicate that macropinocytosis likely facilitates CoV infection through enhanced cell-to-cell spreading. Our studies are the first to demonstrate virus use of macropinocytosis for a role other than entry and suggest a much broader potential exploitation of macropinocytosis in virus replication and host interactions. IMPORTANCE Coronaviruses (CoVs), including severe acute respiratory syndrome (SARS) CoV and Middle East respiratory syndrome CoV, are critical emerging human pathogens. Macropinocytosis is induced by many pathogens to enter host cells, but other functions for macropinocytosis in virus replication are unknown. In this work, we show that CoVs induce a macropinocytosis late in infection that is continuous, independent from cell entry, and associated with increased virus titers and cell fusion. Murine hepatitis virus macropinocytosis requires a fusogenic virus spike protein and signals through the epidermal growth factor receptor and the classical macropinocytosis pathway. These studies demonstrate CoV induction of macropinocytosis for a purpose other than entry and indicate that viruses likely exploit macropinocytosis at multiple steps in replication and pathogenesis.
format	article
author	Megan Culler Freeman Christopher T. Peek Michelle M. Becker Everett Clinton Smith Mark R. Denison
author_facet	Megan Culler Freeman Christopher T. Peek Michelle M. Becker Everett Clinton Smith Mark R. Denison
author_sort	Megan Culler Freeman
title	Coronaviruses Induce Entry-Independent, Continuous Macropinocytosis
title_short	Coronaviruses Induce Entry-Independent, Continuous Macropinocytosis
title_full	Coronaviruses Induce Entry-Independent, Continuous Macropinocytosis
title_fullStr	Coronaviruses Induce Entry-Independent, Continuous Macropinocytosis
title_full_unstemmed	Coronaviruses Induce Entry-Independent, Continuous Macropinocytosis
title_sort	coronaviruses induce entry-independent, continuous macropinocytosis
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/ed2ee7acc73d4ae1857ac8007863e319
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Coronaviruses Induce Entry-Independent, Continuous Macropinocytosis

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