JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells

ABSTRACT The endemic human JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy in immune-suppressed patients. The mechanisms of virus infection in vivo are not understood because the major target cells for virus in the brain do not express virus receptors and do not bind virus....

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Autores principales:	Jenna Morris-Love, Gretchen V. Gee, Bethany A. O’Hara, Benedetta Assetta, Abigail L. Atkinson, Aisling S. Dugan, Sheila A. Haley, Walter J. Atwood
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	progressive multifocal leukoencephalopathy central nervous system infections extracellular vesicle polyomavirus virus receptor Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ed0c2686dfa74786a627a85fd4ae68f3
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spelling	oai:doaj.org-article:ed0c2686dfa74786a627a85fd4ae68f32021-11-15T15:55:24ZJC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells10.1128/mBio.00379-192150-7511https://doaj.org/article/ed0c2686dfa74786a627a85fd4ae68f32019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00379-19https://doaj.org/toc/2150-7511ABSTRACT The endemic human JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy in immune-suppressed patients. The mechanisms of virus infection in vivo are not understood because the major target cells for virus in the brain do not express virus receptors and do not bind virus. We found that JCPyV associates with extracellular vesicles (EVs) and can infect target cells independently of virus receptors. Virus particles were found packaged inside extracellular vesicles and attached to the outer side of vesicles. Anti-JCPyV antisera reduced infection by purified virus but had no effect on infection by EV-associated virus. Treatment of cells with the receptor-destroying enzyme neuraminidase inhibited infection with purified virus but did not inhibit infection by EV-associated virus. Mutant pseudoviruses defective in sialic acid receptor binding could not transduce cells as purified pseudovirions but could do so when associated with EVs. This alternative mechanism of infection likely plays a critical role in the dissemination and spread of JCPyV both to and within the central nervous system. IMPORTANCE JC polyomavirus (JCPyV) is a ubiquitous human pathogen that causes progressive multifocal leukoencephalopathy (PML), a severe and often fatal neurodegenerative disease in immunocompromised or immunomodulated patients. The mechanisms responsible for initiating infection in susceptible cells are not completely known. The major attachment receptor for the virus, lactoseries tetrasaccharide c (LSTc), is paradoxically not expressed on oligodendrocytes or astrocytes in human brain, and virus does not bind to these cells. Because these are the major cell types targeted by the virus in the brain, we hypothesized that alternative mechanisms of infection must be responsible. Here we provide evidence that JCPyV is packaged in extracellular vesicles from infected cells. Infection of target cells by vesicle-associated virus is not dependent on LSTc and is not neutralized by antisera directed against the virus. This is the first demonstration of a polyomavirus using extracellular vesicles as a means of transmission.Jenna Morris-LoveGretchen V. GeeBethany A. O’HaraBenedetta AssettaAbigail L. AtkinsonAisling S. DuganSheila A. HaleyWalter J. AtwoodAmerican Society for Microbiologyarticleprogressive multifocal leukoencephalopathycentral nervous system infectionsextracellular vesiclepolyomavirusvirus receptorMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	progressive multifocal leukoencephalopathy central nervous system infections extracellular vesicle polyomavirus virus receptor Microbiology QR1-502
spellingShingle	progressive multifocal leukoencephalopathy central nervous system infections extracellular vesicle polyomavirus virus receptor Microbiology QR1-502 Jenna Morris-Love Gretchen V. Gee Bethany A. O’Hara Benedetta Assetta Abigail L. Atkinson Aisling S. Dugan Sheila A. Haley Walter J. Atwood JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells
description	ABSTRACT The endemic human JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy in immune-suppressed patients. The mechanisms of virus infection in vivo are not understood because the major target cells for virus in the brain do not express virus receptors and do not bind virus. We found that JCPyV associates with extracellular vesicles (EVs) and can infect target cells independently of virus receptors. Virus particles were found packaged inside extracellular vesicles and attached to the outer side of vesicles. Anti-JCPyV antisera reduced infection by purified virus but had no effect on infection by EV-associated virus. Treatment of cells with the receptor-destroying enzyme neuraminidase inhibited infection with purified virus but did not inhibit infection by EV-associated virus. Mutant pseudoviruses defective in sialic acid receptor binding could not transduce cells as purified pseudovirions but could do so when associated with EVs. This alternative mechanism of infection likely plays a critical role in the dissemination and spread of JCPyV both to and within the central nervous system. IMPORTANCE JC polyomavirus (JCPyV) is a ubiquitous human pathogen that causes progressive multifocal leukoencephalopathy (PML), a severe and often fatal neurodegenerative disease in immunocompromised or immunomodulated patients. The mechanisms responsible for initiating infection in susceptible cells are not completely known. The major attachment receptor for the virus, lactoseries tetrasaccharide c (LSTc), is paradoxically not expressed on oligodendrocytes or astrocytes in human brain, and virus does not bind to these cells. Because these are the major cell types targeted by the virus in the brain, we hypothesized that alternative mechanisms of infection must be responsible. Here we provide evidence that JCPyV is packaged in extracellular vesicles from infected cells. Infection of target cells by vesicle-associated virus is not dependent on LSTc and is not neutralized by antisera directed against the virus. This is the first demonstration of a polyomavirus using extracellular vesicles as a means of transmission.
format	article
author	Jenna Morris-Love Gretchen V. Gee Bethany A. O’Hara Benedetta Assetta Abigail L. Atkinson Aisling S. Dugan Sheila A. Haley Walter J. Atwood
author_facet	Jenna Morris-Love Gretchen V. Gee Bethany A. O’Hara Benedetta Assetta Abigail L. Atkinson Aisling S. Dugan Sheila A. Haley Walter J. Atwood
author_sort	Jenna Morris-Love
title	JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells
title_short	JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells
title_full	JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells
title_fullStr	JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells
title_full_unstemmed	JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells
title_sort	jc polyomavirus uses extracellular vesicles to infect target cells
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/ed0c2686dfa74786a627a85fd4ae68f3
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JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells

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