Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis

Area of Science:

• Neurovirology
• Cell Death Pathways
• Immunology

Background:

• Herpes simplex virus 1 (HSV-1) causes severe neurological diseases like encephalitis.
• Ferroptosis, a nonapoptotic programmed cell death, is implicated in neurological inflammatory diseases.
• The role of ferroptosis in HSV-1 pathogenesis remains unclear.

Purpose of the Study:

• To investigate if HSV-1 induces ferroptosis in the central nervous system (CNS).
• To elucidate the role of ferroptosis in HSV-1 pathogenesis.
• To explore ferroptosis inhibition as a therapeutic strategy for HSV-1 encephalitis.

Main Methods:

• HSV-1 infection of human astrocytes and microglia cells.
• Analysis of ferroptosis hallmarks (Fe2+ overload, ROS, GSH depletion, lipid peroxidation, mitochondrion shrinkage).
• Mouse model of HSV-1 encephalitis with ferroptosis inhibition.

Main Results:

• HSV-1 infection induced ferroptosis in cultured cells and murine brains.
• HSV-1 enhanced Keap1-mediated Nrf2 degradation, promoting ferroptosis.
• Ferroptosis inhibition, via specific inhibitors or proteasome inhibitors, reduced Nrf2 degradation and alleviated HSV-1 encephalitis.
• Upregulation of PTGS2 and PGE2 was linked to ferroptosis and HSV-1-induced inflammation.

Conclusions:

• HSV-1 infection triggers ferroptosis in the CNS.
• HSV-1-induced ferroptosis contributes to encephalitis pathogenesis via Nrf2 pathway dysregulation.
• Targeting ferroptosis presents a promising therapeutic avenue for HSV-1 encephalitis.