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

Michael P Wilczek,Melissa S Maginnis,Francesca J Armstrong,Benjamin L King,Colleen L Mayberry

doi:10.3390/cells10113218

Abstract

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.

Highlights

JC polyomavirus (JCPyV) is a human-specific pathogen and is the causative agent of a fatal disease in the central nervous system (CNS) known as progressive multifocal leukoencephalopathy (PML) [1–4]
In addition to the PI3K/AKT/mechanistic target of rapamycin (mTOR) signaling pathway implicated i6nofJ2C5 PyV in tion [48,50,59], the mitogen-activated protein kinase, extracellular signal-regulated ki (MAPK/ERK) pathway is required for JCPyV infection [61,73,74]
Astrocytes are the main targets of JCPyV infection in the CNS, where the destruction of these cells, along with oligodendrocytes, leads to PML [1–4,26]

Summary

Introduction

JC polyomavirus (JCPyV) is a human-specific pathogen and is the causative agent of a fatal disease in the central nervous system (CNS) known as progressive multifocal leukoencephalopathy (PML) [1–4]. During immunosuppression, JCPyV can reactivate and spread to the CNS [9,12,13], causing the fatal, demyelinating disease PML [1–4]. Due to the immunosuppressive state associated with HIV infection, a large proportion of individuals diagnosed with PML are infected with HIV; due to more effective treatments related to HIV/AIDS, PML incidence is decreasing in this population [14–16]. New risk groups are emerging, with a higher proportion of PML cases diagnosed in patients with hematological malignancies and in patients taking immunomodulatory therapies for immune-mediated diseases [16]. Additional treatment options, including adoptive T cell transfer and checkpoint inhibitors, prolong life expectancy; these treatments are still relatively new, only address the underlying immunosuppression and can result in severe morbidity [19,20,23–25]

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