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IRF-3 activation by Sendai virus infection is required for cellular apoptosis and avoidance of persistence

Kristi Peters1, Saurabh Chattopadhyay, Ganes C Sen

  • 1Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

Journal of Virology
|January 25, 2008
PubMed

Insights

Manipulating cellular responses to virus infection can prevent apoptosis, leading to persistent infections. Interferon regulatory factor-3 (IRF-3) activation is crucial for apoptosis and preventing persistent Sendai virus (SeV) infection.

Area of Science:

  • Virology
  • Immunology
  • Cell Biology

Background:

  • Paramyxoviruses like Sendai virus (SeV) can induce apoptosis in human cell lines.
  • The cellular mechanisms controlling apoptosis during viral infections are complex and not fully understood.

Purpose of the Study:

  • To investigate the role of specific cellular pathways in regulating apoptosis during paramyxovirus infection.
  • To determine if manipulating these pathways can alter the outcome of infection, specifically leading to persistent infections.

Main Methods:

  • Infection of human cell lines with Sendai virus (SeV) or human parainfluenza virus 3.
  • Pharmacological inhibition of phosphatidylinositol 3-kinases (PI3 kinases) in infected cells.
  • Assessment of apoptosis, viral gene expression, and activation of signaling pathways including caspase 8, AKT, JNK, IRF-3, Jak-STAT, and NF-kappaB.
  • Blocking IRF-3 activation or its upstream RIG-I pathway to establish persistent infections.
  • Restoration of apoptosis by introducing IRF-3 into persistently infected cells.

Main Results:

  • SeV and human parainfluenza virus 3 infection induced slow apoptosis, which was accelerated by blocking PI3 kinases.
  • Apoptosis required viral gene expression and the caspase 8 pathway, but not Jak-STAT or NF-kappaB.
  • IRF-3 activation was essential for apoptosis; blocking IRF-3 or RIG-I led to persistent SeV infection.
  • Persistent infection was characterized by sustained viral protein and infectious virus production.
  • Reintroduction of IRF-3 into persistently infected cells restored apoptosis.

Conclusions:

  • Interferon regulatory factor-3 (IRF-3) activation is a critical determinant of cell fate following SeV infection, promoting apoptosis and preventing viral persistence.
  • The PI3K/AKT pathway is involved in regulating the rate of apoptosis but is not essential for IRF-3 activation.
  • IRF-3 acts downstream of RIG-I and controls apoptosis, thereby preventing the establishment of persistent paramyxovirus infections.

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