JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor.

Bethany A O'Hara,Walter J Atwood,Gretchen V Gee,Jenna Morris-Love,Sheila A Haley,David Ornelles

doi:10.1371/journal.ppat.1008371

Bethany A O'Hara, Walter J Atwood + Show 4 more

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https://doi.org/10.1371/journal.ppat.1008371

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Abstract

The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy (PML) in immunosuppressed and immunomodulated patients. Initial infection with JCPyV is common and the virus establishes a long-term persistent infection in the urogenital system of 50–70% of the human population worldwide. A major gap in the field is that we do not know how the virus traffics from the periphery to the brain to cause disease. Our recent discovery that human choroid plexus epithelial cells are fully susceptible to virus infection together with reports of JCPyV infection of choroid plexus in vivo has led us to hypothesize that the choroid plexus plays a fundamental role in this process. The choroid plexus is known to relay information between the blood and the brain by the release of extracellular vesicles. This is particularly important because human macroglia (oligodendrocytes and astrocytes), the major targets of virus infection in the central nervous system (CNS), do not express the known attachment receptors for the virus and do not bind virus in human tissue sections. In this report we show that JCPyV infected choroid plexus epithelial cells produce extracellular vesicles that contain JCPyV and readily transmit the infection to human glial cells. Transmission of the virus by extracellular vesicles is independent of the known virus attachment receptors and is not neutralized by antisera directed at the virus. We also show that extracellular vesicles containing virus are taken into target glial cells by both clathrin dependent endocytosis and macropinocytosis. Our data support the hypothesis that the choroid plexus plays a fundamental role in the dissemination of virus to brain parenchyma.

Highlights

JC polyomavirus (JCPyV), a human polyomavirus, establishes a lifelong persistent infection in over half the world’s population [1]
JC polyomavirus (JCPyV) is a common human pathogen that causes a central nervous system demyelinating disease known as progressive multifocal leukoencephalopathy
In previous work we found that choroid plexus epithelial cells express receptors for JCPyV in vivo and are fully susceptible to virus infection in vitro

Summary

Introduction

JCPyV, a human polyomavirus, establishes a lifelong persistent infection in over half the world’s population [1]. Cell culture models using purified JCPyV virions have shown that the virus requires the sialic acid-containing attachment receptor, lactoseries tetrasaccharide C (LSTc), to bind target cells [12,13,14,15]. Neither oligodendrocytes nor astrocytes, the major targets of virus infection in the CNS, express the attachment receptor and neither bind virus [17]. This is consistent with the accumulation of mutations in the sialic acid binding pocket of the virus found in the CSF and brain parenchyma of patients with PML [18,19,20]. This observation suggests that there is no selective pressure to maintain the sialic acid binding phenotype once virus has invaded brain parenchyma

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