Susceptibility of Primary Human Choroid Plexus Epithelial Cells and Meningeal Cells to Infection by JC Virus

Abstract

JC polyomavirus (JCPyV) establishes a lifelong persistence in roughly half the human population worldwide. The cells and tissues that harbor persistent virus are not known, but renal tubules and other urogenital epithelial cells are likely candidates as virus is shed in the urine of healthy individuals. In an immunosuppressed host, JCPyV can become reactivated and cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system. Recent observations indicate that JCPyV may productively interact with cells in the choroid plexus and leptomeninges. To further study JCPyV infection in these cells, primary human choroid plexus epithelial cells and meningeal cells were challenged with virus, and their susceptibility to infection was compared to the human glial cell line, SVG-A. We found that JCPyV productively infects both choroid plexus epithelial cells and meningeal cells Competition with the soluble receptor fragment LSTc reduced virus infection in these cells. Treatment of cells with neuraminidase also inhibited both viral infection and binding. Treatment with the serotonin receptor antagonist, ritanserin, reduced infection in SVG-A and meningeal cells. We also compared the ability of wild-type and sialic acid-binding mutant pseudoviruses to transduce these cells. Wild-type pseudovirus readily transduced all three cell types, but pseudoviruses harboring mutations in the sialic acid-binding pocket of the virus failed to transduce the cells. These data establish a novel role for choroid plexus and meninges in harboring virus that likely contributes not only to meningoencephalopathies but also to PML. JCPyV infects greater than half the human population worldwide and causes central nervous system disease in patients with weakened immune systems. Several recent reports have found JCPyV in the choroid plexus and leptomeninges of patients with encephalitis. Due to their role in forming the blood-cerebrospinal fluid barrier, the choroid plexus and leptomeninges are also poised to play roles in virus invasion of brain parenchyma, where infection of macroglial cells leads to the development of progressive multifocal leukoencephalopathy, a severely debilitating and often fatal infection. In this paper we show for the first time that primary choroid plexus epithelial cells and meningeal cells are infected by JCPyV, lending support to the association of JCPyV with meningoencephalopathies. These data also suggest that JCPyV could use these cells as reservoirs for the subsequent invasion of brain parenchyma.

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

“…Our hypothesis is supported by the in vivo demonstration of JCPyV infected choroid plexus epithelial cells and meningeal cells from a patient with meningitis and from several patients with PML [28,29]. We also previously reported that the choroid plexus, like cells in the kidney, express the JCPyV attachment and entry receptors, bind virus in human tissue sections, and are completely susceptible to virus infection in vitro [17,27]. This is in contrast to human macroglial cells that do not express the critical attachment receptor for the virus and do not bind virus in human tissue sections [17].…”

“…JCPyV to human glia in EV independently of the known sialic acid attachment receptor LSTc [22,[26][27][28][29][30]. To study the role of choroid plexus derived extracellular vesicles in dissemination of JCPyV to the CNS in depth we immortalized primary human choroid plexus epithelial cells with human telomerase (hTert) and showed that they maintain the properties of the primary cells.…”

BK virus encephalitis and end‐stage renal disease in a child with hematopoietic stem cell transplantation

“…During states of immunosuppression, it is possible for the latent CNS BK virus to reactivate and cause meningoencephalitis 10 . In fact, JC virus has been shown to infect the primary choroid plexus epithelial cells and meningeal cells, using these cells as reservoirs for the subsequent invasion of brain parenchyma 12 . However, since BK virus DNA has been detected in the brain tissue and CSF of immunocompetent individuals as well, a mere presence of virus is not a proof of a causal relationship between neurological symptoms and the virus 13‐15 .…”

Zika virus infects pericytes in the choroid plexus and enters the central nervous system through the blood-cerebrospinal fluid barrier

“…A very limited number of studies have been conducted with CP epithelial cells with respect to neuroinvasion. John Cunningham virus and Chikungunya virus are known to infect CP epithelial cells in vitro (37,68); however, to our knowledge, our study shows for the first time neurotropic viruses traversing the CP epithelial cell layers without active replication. Importantly, interferon gamma (IFN-γ), the Th2-type cytokine interleukin-4 (IL-4), and MPC-1 are known to enhance transcytosis of IgA and HIV (69,70).…”