Replication of JC Virus DNA in the G144 Oligodendrocyte Cell Line Is Dependent Upon Akt

Peterson, Julia; Lin, Brian M.; Shin, Jong; Phelan, Paul J.; Tsichlis, Philip N.; Schwob, James E.; Bullock, Peter A.

doi:10.1128/jvi.00735-17

Cited by 6 publications

(8 citation statements)

References 107 publications

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“…Given the specificity of the virus to the human host, in vitro systems using human cell lines are critical for understanding viral infection and pathogenesis. Previous to this study, JCPyV infection in vitro has been limited to cell types found in human brain parenchymal cells, including the cell lines derived from human fetal glial cells, SVG and SVG-A (60-63), progenitor-derived astrocytes (64)(65)(66), hESC-derived oligodendrocyte progenitors (67), glial progenitor cells and astrocytes (68), and a recently described glioblastoma-derived oligodendrocyte precursor line (69). These cells do not always proliferate well and have varying degrees of virus susceptibility.…”

Section: Figmentioning

confidence: 99%

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

O’Hara

Gee

Atwood

et al. 2018

J Virol

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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.

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Section: Figmentioning

confidence: 99%

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

O’Hara

Gee

Atwood

et al. 2018

J Virol

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“…The PI3K/AKT/mTOR signaling pathway has been previously implicated in other polyomavirus infections as well [48,50,59,[89][90][91][92]. Earlier research has demonstrated that the BK polyomavirus (BKPyV), murine polyomavirus, and JCPyV influence the PI3K/AKT signaling pathway by modulating the cellular phosphatase, protein phosphatase 2A (PP2A) [89][90][91].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the PI3K/AKT/mTOR signaling pathway implicated in JCPyV infection [48,50,59], the mitogen-activated protein kinase, extracellular signal-regulated kinase (MAPK/ERK) pathway is required for JCPyV infection [61,73,74]. This pathway is temporally regulated, specifically being phosphorylated upon JCPyV infection, and infection of immortalized cells is significantly reduced when cells are treated with ERK siRNAs or inhibitors [61,66,73,74].…”

Section: U0126 a Common Mek Inhibitor Does Not Reduce Jcpyv Infection...mentioning

confidence: 99%

“…Previous research has demonstrated that the PI3K/AKT signaling pathway, specifically the AKT and PI3Kγ steps, is required for JCPyV infection in SVGAs and an oligodendrocyte cell line [48,59,82]. To determine if this pathway is implicated in JCPyV infection in NHAs, RNA-seq data was analyzed [66] over the course of JCPyV infection in NHAs and SVGAs.…”

Section: Pi3k/akt Signaling Pathway Genes Are Upregulated During Jcpy...mentioning

confidence: 99%

“…Along with the diverse drugs targeting this pathway and their ability to traverse the BBB, they have also been implicated in JCPyV infection, contributing to a framework for future PML therapeutics. MK2206 has been demonstrated to reduce JCPyV DNA replication in an oligodendrocyte cell line [59]; however, mTOR inhibitors, such as rapamycin, increased expression of JCPyV T Ag in an immortalized kidney cell line-human embryonic kidney (HEK) 293 cells [50]. Due to these recent findings, the lack of an effective treatment for PML, and observed differences in JCPyV infection in immortalized cells, components of the PI3K/AKT/mTOR signaling pathway were analyzed through RNA sequencing (RNA-seq) analysis, and chemical inhibitors that target this signaling pathway were examined for their capacity to reduce JCPyV infection.…”

Section: Introductionmentioning

confidence: 99%

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PI3K/AKT/mTOR Signaling Pathway Is Required for JCPyV Infection in Primary Astrocytes

Wilczek

Armstrong

Mayberry

et al. 2021

Cells

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Astrocytes are a main target of JC polyomavirus (JCPyV) in the central nervous system (CNS), where the destruction of these cells, along with oligodendrocytes, leads to the fatal disease progressive multifocal leukoencephalopathy (PML). There is no cure currently available for PML, so it is essential to discover antivirals for this aggressive disease. Additionally, the lack of a tractable in vivo models for studying JCPyV infection makes primary cells an accurate alternative for elucidating mechanisms of viral infection in the CNS. This research to better understand the signaling pathways activated in response to JCPyV infection reveals and establishes the importance of the PI3K/AKT/mTOR signaling pathway in JCPyV infection in primary human astrocytes compared to transformed cell lines. Using RNA sequencing and chemical inhibitors to target PI3K, AKT, and mTOR, we have demonstrated the importance of this signaling pathway in JCPyV infection of primary astrocytes not observed in transformed cells. Collectively, these findings illuminate the potential for repurposing drugs that are involved with inhibition of the PI3K/AKT/mTOR signaling pathway and cancer treatment as potential therapeutics for PML, caused by this neuroinvasive virus.

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A human-derived 3D brain organoid model to study JC virus infection

et al. 2022

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Progressive multifocal leukoencephalopathy (PML) is a frequent neurological complication in immunosuppressed patients. PML is caused by the JC virus (JCV), a neurotropic DNA polyomavirus that infects oligodendrocytes and astrocytes, causing inflammation and demyelination which lead to neurological dysfunction. The pathogenesis of PML is poorly understood due to the lack of in vitro or animal models to study mechanisms of disease as the virus most efficiently infects only human cells. We developed a human-derived brain organotypic system (also called brain organoid) to model JCV infection. The model was developed by using human-induced pluripotent stem cells (iPSC) and culturing them in 3D to generate an organotypic model containing neurons, astrocytes, and oligodendrocytes which recapitulates aspects of the environment of the human brain. We infected the brain organoids with the JCV MAD4 strain or cerebrospinal fluid of a patient with PML. The organoids were assessed for evidence of infection by qPCR, immunofluorescence, and electron microscopy at 1, 2, and 3 weeks post-exposure. JCV infection in both JCV MAD4 strain and PML CSF-exposed brain organoids was confirmed by immunocytochemical studies demonstrating viral antigens and electron microscopy showing virion particles in the nuclear compartment of oligodendrocytes and astrocytes. No evidence of neuronal infection was visualized. Infection was also demonstrated by JCV qPCR in the virus-exposed organoids and their media. In conclusion, the brain organoid model of JCV infection establishes a human model suitable for studying the mechanisms of JCV infection and pathogenesis of PML and may facilitate the exploration of therapeutic approaches.

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Replication of JC Virus DNA in the G144 Oligodendrocyte Cell Line Is Dependent Upon Akt

Cited by 6 publications

References 107 publications

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

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

PI3K/AKT/mTOR Signaling Pathway Is Required for JCPyV Infection in Primary Astrocytes

A human-derived 3D brain organoid model to study JC virus infection

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