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

Dana May1, Anna Bellizzi1, Workineh Kassa2

  • 1Department of Neuroscience, Center for Neurovirology-Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.

Viruses
|October 26, 2021
PubMed

Insights

Interferon-alpha (IFNα) and interferon-beta (IFNβ) suppress JC polyomavirus (JCPyV) replication by increasing liver inhibitory protein (LIP), an isoform of C/EBPβ. This mechanism may control JCPyV latency and reactivation in PML.

Area of Science:

  • Virology
  • Immunology
  • Neuroscience

Background:

  • JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease.
  • JCPyV reactivation under immunosuppression is linked to glial cell infection and viral gene expression.
  • Tumor necrosis factor-alpha (TNF-α) stimulates JCPyV transcription, but regulatory mechanisms remain incompletely understood.

Purpose of the Study:

  • To investigate the role of interferon-alpha (IFNα) and interferon-beta (IFNβ) in regulating JCPyV transcription and replication.
  • To elucidate the mechanism by which interferons exert their regulatory effects on JCPyV.
  • To determine the involvement of C/EBPβ-LIP in interferon-mediated JCPyV suppression.

Main Methods:

  • Treatment of glial cell lines with IFNα or IFNβ.
  • Analysis of JCPyV transcriptional regulation and viral replication.
  • Assessment of C/EBPβ-LIP expression levels.
  • Knockdown of C/EBPβ-LIP using short hairpin RNA (shRNA).

Main Results:

  • IFNα and IFNβ were found to negatively regulate JCPyV transcriptional regulation.
  • Interferons induce the expression of liver inhibitory protein (LIP), an isoform of C/EBPβ, in glial cells.
  • The inhibitory effect of interferons on JCPyV transcription and replication is enhanced by C/EBPβ-LIP.
  • Knockdown of C/EBPβ-LIP reversed the inhibitory effects of interferons on JCPyV replication.

Conclusions:

  • IFNα and IFNβ negatively regulate JCPyV through the induction of C/EBPβ-LIP.
  • C/EBPβ-LIP plays a critical role in mediating the antiviral effects of interferons against JCPyV.
  • This interferon-C/EBPβ-LIP pathway may be a key factor in controlling the balance between JCPyV latency and reactivation.
Keywords:
C/EBPβ-LIPCRISPR Cas9 STAT-1 knockoutinterferonα and β signalingpolyomavirus JCprogressive multifocal leukoencephalopathy

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