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Japanese encephalitis virus down-regulates thioredoxin and induces ROS-mediated ASK1-ERK/p38 MAPK activation in human

Tsuey-Ching Yang1, Chien-Chen Lai, Su-Lian Shiu

  • 1Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.

Microbes and Infection
|May 1, 2010
PubMed

Insights

Japanese encephalitis virus (JEV) triggers apoptosis via oxidative stress. Down-regulation of thioredoxin and activation of ASK1-ERK/p38 MAPK signaling are key mechanisms in JEV pathogenesis.

Area of Science:

  • Virology
  • Molecular Biology
  • Cellular Biology

Background:

  • Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus causing severe neurological disease and high mortality.
  • The precise molecular mechanisms underlying JEV pathogenesis, particularly apoptotic pathways, remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms of JEV-induced apoptosis in human promonocyte cells.
  • To identify key cellular pathways involved in JEV pathogenesis.

Main Methods:

  • JEV infection of human promonocyte cells.
  • Time-dependent analysis of apoptosis and caspase activation (caspases 3, 8, and 9).
  • Proteomic analysis to identify differentially expressed proteins.
  • Western blotting to confirm protein expression (thioredoxin).
  • Measurement of intracellular reactive oxygen species (ROS) production.
  • Analysis of ASK1-ERK/p38 MAPK signaling pathway activation.
  • Inhibition of ERK/p38 MAPK signaling using PD98059.

Main Results:

  • JEV infection induced time-dependent apoptosis and dose-dependent activation of caspases 3, 8, and 9.
  • Proteomic analysis revealed significant up- and down-regulation of proteins involved in antioxidation, free radical removal, and sulfur redox metabolism.
  • Down-regulation of thioredoxin was confirmed and linked to the oxidative stress response pathway in apoptosis.
  • JEV infection led to increased intracellular ROS production and activation of the ASK1-ERK/p38 MAPK signaling pathway.
  • Inhibition of ERK/p38 MAPK signaling suppressed JEV-induced apoptosis.

Conclusions:

  • JEV-induced apoptosis involves oxidative stress, characterized by thioredoxin down-regulation and increased ROS production.
  • The ASK1-ERK/p38 MAPK signaling pathway is activated during JEV infection and contributes to apoptosis.
  • Oxidative stress and associated signaling pathways represent a critical component of Japanese encephalitis pathogenesis.

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