Interferon regulatory factors 3 and 7 have distinct roles in the pathogenesis of alphavirus encephalomyelitis

Kimberly L.W. Schultz, Elizabeth M. Troisi, Victoria K. Baxter, Rebecca Glowinski, Diane E. Griffin

Research output: Contribution to journalArticlepeer-review

Abstract

Interferon (IFN) regulatory factors (IRFs) are important determinants of the innate response to infection. We evaluated the role(s) of combined and individual IRF deficiencies in the outcome of infection of C57BL/6 mice with Sindbis virus, an alphavirus that infects neurons and causes encephalomyelitis. The brain and spinal cord levels of Irf7, but not Irf3 mRNAs, were increased after infection. IRF3/5/7−/− and IRF3/7−/− mice died within 3–4 days with uncontrolled virus replication, similar to IFNα receptor-deficient mice, while all wild-type (WT) mice recovered. IRF3−/− and IRF7−/− mice had brain levels of IFNα that were lower, but brain and spinal cord levels of IFNβ and IFN-stimulated gene mRNAs that were similar to or higher than WT mice without detectable serum IFN or increases in Ifna or Ifnb mRNAs in the lymph nodes, indicating that the differences in outcome were not due to deficiencies in the central nervous system (CNS) type I IFN response. IRF3−/− mice developed persistent neurological deficits and had more spinal cord inflammation and higher CNS levels of Il1b and Ifnγ mRNAs than WT mice, but all mice survived. IRF7−/− mice died 5–8 days after infection with rapidly progressive paralysis and differed from both WT and IRF3−/− mice in the induction of higher CNS levels of IFNβ, tumour necrosis factor (TNF) α and Cxcl13 mRNA, delayed virus clearance and more extensive cell death. Therefore, fatal disease in IRF7−/− mice is likely due to immune-mediated neurotoxicity associated with failure to regulate the production of inflammatory cytokines such as TNFα in the CNS.

Original languageEnglish (US)
Article number001174
Pages (from-to)46-62
Number of pages17
JournalJournal of General Virology
Volume100
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • CNS inflammation
  • CXCL13
  • Cell death
  • Mice
  • Sindbis virus
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Virology

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