Differentiation of neurons restricts arbovirus replication and increases expression of the alpha isoform of IRF-7

Kimberly L W Schultz, Patty S. Vernon, Diane Griffin

Research output: Contribution to journalArticle

Abstract

Susceptibility to alphavirus infection is age dependent, and host maturation is associated with decreased virus replication and less severe encephalitis. To identify factors associated with maturation-dependent restriction of virus replication, we studied AP-7 rat olfactory bulb neuronal cells, which can differentiate in vitro. Differentiation was associated with a 150- to 1,000-fold decrease in replication of the alphaviruses Sindbis virus and Venezuelan equine encephalitis virus, as well as La Crosse bunyavirus. Differentiation delayed synthesis of SINV RNA and protein but did not alter the susceptibility of neurons to infection or virion maturation. Additionally, differentiation slowed virus-induced translation arrest and death of infected cells. Differentiation of uninfected AP-7 neurons was associated with changes in expression of antiviral genes. Expression of key transcription factors was increased, including interferon regulatory factor 3 and 7 (IRF-3 and IRF-7) and STAT-1, suggesting that neuronal maturation may enhance the capacity for antiviral signaling upon infection. IRF-7 produced by undifferentiated AP-7 neurons was exclusively the short dominant negative γ-isoform, while that produced by differentiated neurons was the full-length α-isoform. A similar switch in IRF-7 isoforms also occurred in the brains of maturing C57BL/6J mice. Silencing of IRF expression did not improve virus multiplication in differentiated neurons. Therefore, neuronal differentiation is associated with upregulation of transcription factors that activate antiviral signaling, but this alone does not account for maturation-dependent restriction of virus replication.

Original languageEnglish (US)
Pages (from-to)48-60
Number of pages13
JournalJournal of Virology
Volume89
Issue number1
DOIs
StatePublished - 2015

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Arboviruses
arboviruses
Protein Isoforms
neurons
Neurons
Virus Replication
Antiviral Agents
virus replication
Alphavirus
Alphavirus Infections
Interferon Regulatory Factor-7
Transcription Factors
Orthobunyavirus
Venezuelan Equine Encephalitis Viruses
Interferon Regulatory Factor-3
Sindbis Virus
Viruses
transcription factors
Sindbis virus
Venezuelan equine encephalitis virus

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Differentiation of neurons restricts arbovirus replication and increases expression of the alpha isoform of IRF-7. / Schultz, Kimberly L W; Vernon, Patty S.; Griffin, Diane.

In: Journal of Virology, Vol. 89, No. 1, 2015, p. 48-60.

Research output: Contribution to journalArticle

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