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IRF3 polymorphisms induce different innate anti-Theiler's virus immune responses in RAW264.7 macrophages

Tyler C Moore1, Fahd M Al-Salleeh, Deborah M Brown

  • 1School of Biological Sciences, University of Nebraska Lincoln, Lincoln, NE 68583-0740, USA.

Virology
|August 4, 2011
PubMed

Insights

Genetic variations in the Interferon Regulatory Factor 3 (IRF3) protein influence how mice respond to Theiler's murine encephalomyelitis virus (TMEV). These IRF3 differences impact viral persistence and inflammatory cytokine production, affecting disease outcomes.

Area of Science:

  • Immunology
  • Virology
  • Genetics

Background:

  • Persistent viral infections, like those caused by Theiler's murine encephalomyelitis virus (TMEV), can lead to serious diseases such as myocarditis and demyelinating conditions.
  • Theiler's murine encephalomyelitis virus (TMEV) establishes persistent infections in SJL/J mice but is cleared by B10.S mice, both of which are H-2s haplotype.
  • Interferon Regulatory Factor 3 (IRF3) activation is crucial for inducing antiviral responses (IFNβ, ISG56) and apoptosis, but also pro-inflammatory cytokines (IL-23, IL6) that can exacerbate disease.

Purpose of the Study:

  • To investigate the role of polymorphisms in the Interferon Regulatory Factor 3 (IRF3) gene between SJL/J and B10.S mice in the context of Theiler's murine encephalomyelitis virus (TMEV) infection.
  • To determine how specific IRF3 variants affect viral replication, cytokine expression, and apoptosis in macrophages.

Main Methods:

  • Identification of polymorphisms within the DNA binding, nuclear localization, and autoinhibitory domains of IRF3 in SJL/J and B10.S mice.
  • Expression of SJL-IRF3 and B10S-IRF3 in RAW264.7 macrophage cells.
  • Assessment of IL-23p19 promoter activity, IL-6, IFNβ, ISG56 expression, viral RNA levels, and caspase activation in TMEV-infected macrophages expressing different IRF3 variants.

Main Results:

  • SJL-IRF3 expression decreased IL-23p19 promoter activity but increased IL-6, ISG56, and IFNβ in response to TMEV compared to B10S-IRF3.
  • B10S-IRF3 expression enhanced apoptotic caspase activation and reduced viral RNA in TMEV-infected macrophages.
  • Conversely, SJL-IRF3 expression led to increased viral replication with diminished caspase activation.

Conclusions:

  • Polymorphisms in IRF3 between SJL/J and B10.S mice significantly influence the host's response to TMEV infection.
  • These IRF3 variations contribute to the establishment of viral persistence and modulate the expression of key inflammatory cytokines, impacting disease pathogenesis.
  • Targeting IRF3 or its downstream pathways could offer therapeutic strategies for managing persistent viral infections and associated inflammatory diseases.

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