The MAPK/ERK Pathway and the Role of DUSP1 in JCPyV Infection of Primary Astrocytes.

Michael P Wilczek,Francesca J Armstrong,Colleen L Mayberry,Remi P Geohegan,Benjamin L King,Jeanne K Dushane,Melissa S Maginnis

doi:10.3390/v13091834

Michael P Wilczek, Francesca J Armstrong + Show 5 more

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https://doi.org/10.3390/v13091834

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Journal: Viruses	Publication Date: Sep 14, 2021
Citations: 7	License type: CC BY 4.0

Affiliation: University of Maine

Abstract

JC polyomavirus (JCPyV) is a neuroinvasive pathogen causing a fatal, demyelinating disease of the central nervous system (CNS) known as progressive multifocal leukoencephalopathy (PML). Within the CNS, JCPyV predominately targets two cell types: oligodendrocytes and astrocytes. The underlying mechanisms of astrocytic infection are poorly understood, yet recent findings suggest critical differences in JCPyV infection of primary astrocytes compared to a widely studied immortalized cell model. RNA sequencing was performed in primary normal human astrocytes (NHAs) to analyze the transcriptomic profile that emerges during JCPyV infection. Through a comparative analysis, it was validated that JCPyV requires the mitogen-activated protein kinase, extracellular signal-regulated kinase (MAPK/ERK) pathway, and additionally requires the expression of dual-specificity phosphatases (DUSPs). Specifically, the expression of DUSP1 is needed to establish a successful infection in NHAs, yet this was not observed in an immortalized cell model of JCPyV infection. Additional analyses demonstrated immune activation uniquely observed in NHAs. These results support the hypothesis that DUSPs within the MAPK/ERK pathway impact viral infection and influence potential downstream targets and cellular pathways. Collectively, this research implicates DUSP1 in JCPyV infection of primary human astrocytes, and most importantly, further resolves the signaling events that lead to successful JCPyV infection in the CNS.

Highlights

JC polyomavirus (JCPyV) is a human-specific virus that infects astrocytes and oligodendrocytes, leading to the fatal, demyelinating disease, progressive multifocal leukoencephalopathy (PML) [1,2,3,4,5]
SVGAs were used as a reference cell line and to further define cell-type dependent differences that revealed a delay in JCPyV infection in normal human astrocytes (NHAs) [32]
There was no difference in early gene transcript between NHAs and SVGAs at 24 hpi, a significant increase in late gene transcript was only observed in SVGAs at 48 hpi, and VP1 production was more notably produced in

Summary

Introduction

JC polyomavirus (JCPyV) is a human-specific virus that infects astrocytes and oligodendrocytes, leading to the fatal, demyelinating disease, progressive multifocal leukoencephalopathy (PML) [1,2,3,4,5]. While there have been advancements in treatment, which address the underlying immunosuppression aligned with supportive care, resulting in improved survival rates, a sufficient cure for the disease is still lacking [16,17,18,19]. Beyond these therapies, research has demonstrated that JCPyV encodes microRNAs (miRNAs) [20]

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