IFNα and β Mediated JCPyV Suppression through C/EBPβ-LIP Isoform.

Dana May,Anna Bellizzi,Maurizio Caocci,Hassen S. Wollebo,Workineh Kassa,John M. Cipriaso

doi:10.3390/v13101937

Dana May, Anna Bellizzi + Show 4 more

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https://doi.org/10.3390/v13101937

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Journal: Viruses	Publication Date: Sep 26, 2021
Citations: 4	License type: CC BY 4.0

Affiliation: Temple University, Mayo Clinic Hospital

Abstract

Polyomavirus JC (JCPyV) causes the demyelinating disease progressive multifocal leukoencephalopathy (PML). JCPyV infection is very common in childhood and, under conditions of severe immunosuppression, JCPyV may reactivate to cause PML. JC viral proteins expression is regulated by the JCPyV non-coding control region (NCCR), which contains binding sites for cellular transcriptional factors which regulate JCPyV transcription. Our earlier studies suggest that JCPyV reactivation occurs within glial cells due to cytokines such as TNF-α which stimulate viral gene expression. In this study, we examined interferon-α (IFNα) or β (IFNβ) which have a negative effect on JCPyV transcriptional regulation. We also showed that these interferons induce the endogenous liver inhibitory protein (LIP), an isoform of CAAT/enhancer binding protein beta (C/EBPβ). Treatment of glial cell line with interferons increases the endogenous level of C/EBPβ-LIP. Furthermore, we showed that the negative regulatory role of the interferons in JCPyV early and late transcription and viral replication is more pronounced in the presence of C/EBPβ-LIP. Knockdown of C/EBPβ-LIP by shRNA reverse the inhibitory effect on JCPyV viral replication. Therefore, IFNα and IFNβ negatively regulate JCPyV through induction of C/EBPβ-LIP, which together with other cellular transcriptional factors may control the balance between JCPyV latency and activation.

Highlights

We showed that JCPyV non-coding control region (NCCR) contains a single functional kB element that binds C/EBPβ-liver inhibitory protein (LIP) and mediates inhibition of JCPyV early and late promoter [10]
In a time-dependent experiment, we observed a significant increase of LIP exprtheesspiroenseanfcteerof3t6he(ptw=o0g.0R0N1A1)s adnetder2m4inhed(pa
We reported as supplementary data (Supplementary Figure S1) the endogenous expression of the three C/EBPβ isoforms: full length (FL), liver activating protein (LAP), and liver inhibitory protein (LIP)

Summary

Introduction

Neurotropic Polyomavirus JC (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a severe and often lethal demyelinating disease of the central nervous system (CNS). In PML, JCPyV actively replicates in the glial cells of the CNS (oligodendrocytes and astrocytes) causing lytic cell death and leading to the formation of multiple expanding lesions of demyelination in the brain and worsening neurological dysfunction [1,2]. Despite the occurrence of JCPyV infection in the worldwide population being very common, PML occurs infrequently, and it is almost always found in individuals with severe immune system dysfunction, HIV-1/AIDS, where PML remains a complication even after the prevalent use of combination antiretroviral therapy [3].

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