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Neuronal cell death in alphavirus encephalomyelitis.

D E Griffin1

  • 1W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St, Rm E5132, Baltimore, MD 21205, USA. dgriffin@jhsph.edu

Current Topics in Microbiology and Immunology
|March 29, 2005
PubMed
Summary

Sindbis virus (SINV) causes fatal neurological disease in young animals by inducing apoptosis in immature neurons. Cell death pathways can be blocked by antioxidants, caspase inhibitors, or glutamate receptor antagonists.

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Area of Science:

  • Neuroscience
  • Virology
  • Immunology

Background:

  • Alphaviruses, such as Sindbis virus (SINV), are mosquito-borne RNA viruses causing diverse human diseases, including neurological conditions.
  • SINV serves as a model for alphavirus-induced neurological disease, primarily targeting central nervous system (CNS) neurons.
  • Susceptibility to fatal SINV disease is higher in young animals, linked to apoptosis induction in immature neurons.

Purpose of the Study:

  • To investigate the mechanisms of SINV-induced neuronal cell death in the CNS.
  • To identify host and viral factors influencing neuronal fate during SINV infection.
  • To explore therapeutic strategies for preventing SINV-induced neurological damage.

Main Methods:

  • In vitro studies using neuroblastoma cells to examine viral fusion-induced apoptosis.

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  • Analysis of apoptotic pathways, including acid sphingomyelinase, ceramide, poly(ADP-ribose) polymerase, cytochrome c, and caspases.
  • In vivo studies in young and old mice to compare disease outcomes and neuronal death mechanisms (apoptosis vs. necrosis).
  • Evaluation of preventative treatments, including antioxidants, caspase inhibitors, Bcl-2, Beclin-1, protease inhibitors, and glutamate receptor antagonists.

    • Main Results:

    • SINV-induced apoptosis in immature neurons involves viral envelope fusion with endosomal membranes, activating acid sphingomyelinase and ceramide production.
    • The apoptotic cascade includes poly(ADP-ribose) polymerase activation, cytochrome c release, and effector caspase activation.
    • Young animals exhibit higher susceptibility due to SINV-induced apoptosis in immature neurons, while older animals may experience necrosis in motor neurons or mixed death in hippocampal neurons.
    • Neuronal death in surrounding uninfected neurons was also observed and could be mitigated.

    Conclusions:

    • SINV triggers neuronal apoptosis through a specific molecular pathway initiated by viral fusion and ceramide generation.
    • Therapeutic interventions targeting apoptotic pathways (antioxidants, caspase inhibitors) or excitotoxicity (glutamate antagonists) can prevent or delay SINV-induced neuronal death.
    • Understanding these mechanisms is crucial for developing treatments against alphavirus-induced neurological diseases.