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Inhibition of virus-induced neuronal apoptosis by Bax

Nature Medicine volume 5, pages 832–835 (1999)Cite this article

Abstract

The Bax protein is widely known as a pro-apoptotic Bcl-2 family member that when overexpressed can trigger apoptosis in multiple cell types and is important for the developmental cell death of neurons1,2. However, Bax was found here to be a potent inhibitor of neuronal cell death in mice infected with Sindbis virus. Newborn mice, which are highly susceptible to a fatal infection with neurotropic Sindbis virus, were significantly protected from neuronal apoptosis and fatal disease when infected with a recombinant Sindbis virus encoding Bax. Deletion of the N terminus of Bax, which mimics cleaved Bax, converted Bax into a pro-apoptotic factor in vivo. As mice mature during the first week after birth, they acquire resistance to a fatal Sindbis virus infection3,4. However, Bax-deficient mice remained very sensitive to fatal disease compared with their control littermates, indicating that endogenous Bax functions as a survival factor and contributes to age-dependent resistance to Sindbis virus-induced mortality. The protective effects of Bax were reproduced in cultured hippocampal neurons but not in cultured dorsal root ganglia neurons. These findings indicate that cell-specific factors determine the anti-apoptotic versus pro-apoptotic function of Bax.

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Figure 1: Overexpression of Bax protects mice from a fatal Sindbis virus infection.
Figure 2: Mice deficient in bax show increased neuronal apoptosis and increased susceptibility to a fatal Sindbis virus infection.
Figure 3: Tissue sections from brains of bax+/+ and bax–/– mice 4 d after infection with SV-Bax-reverse.
Figure 4: Neuron-specific function of Bax.

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Acknowledgements

This work was supported by research grant NS34175 (J.M.H.) from the National Institutes of Health and a career development award from the Burroughs Wellcome Foundation (G.A.O.).

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Authors and Affiliations

  1. Department of Pharmacology and Molecular Sciences, Johns Hopkins University Schools of Medicine and Public Health, E5132, SPH, 615 North Wolfe St., Baltimore, 21205, Maryland, USA

    Jennifer Lewis, Yih-Ru Fannjiang, B. Nelson Chau & J. Marie Hardwick

  2. Department of Neurology, Johns Hopkins University Schools of Medicine and Public Health, E5132, SPH, 615 North Wolfe St., Baltimore, 21205, Maryland, USA

    George A. Oyler, James Vornov & J. Marie Hardwick

  3. Department of Molecular Microbiology and Immunology, Johns Hopkins University Schools of Medicine and Public Health, E5132, SPH, 615 North Wolfe St., Baltimore, 21205, Maryland, USA

    Shifa Zou & J. Marie Hardwick

  4. Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan

    Kazuyoshi Ueno

  5. Department of Pathology and Medicine, Dana-Farber Cancer Insitute Harvard Medical School, 44 Binney St., Boston, 02115, Massachusetts, USA

    Stanley J. Korsmeyer

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  1. Jennifer Lewis
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Correspondence to J. Marie Hardwick.

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Lewis, J., Oyler, G., Ueno, K. et al. Inhibition of virus-induced neuronal apoptosis by Bax. Nat Med 5, 832–835 (1999). https://doi.org/10.1038/10556

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