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Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
Published on: June 29, 2011
Inhibition of virus-induced neuronal apoptosis by Bax
1Department of Pharmacology and Molecular Sciences, Johns Hopkins University Schools of Medicine and Public Health, Baltimore, Maryland 21205, USA.
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 neurons. 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 infection. 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.
Insights
Bax protein normally promotes cell death but surprisingly inhibits neuronal death in Sindbis virus infections. Endogenous Bax acts as a survival factor, crucial for age-dependent resistance to fatal viral encephalitis.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Bax protein is a well-established pro-apoptotic member of the Bcl-2 family.
- Overexpression of Bax typically induces apoptosis across various cell types.
- Bax plays a role in developmental neuronal cell death.
Purpose of the Study:
- To investigate the role of Bax in neuronal cell death during Sindbis virus infection.
- To determine if Bax exhibits anti-apoptotic or pro-apoptotic functions in vivo and in vitro.
- To elucidate the mechanism behind Bax's function in viral encephalitis.
Main Methods:
- Infection of newborn mice with Sindbis virus, including recombinant viruses encoding Bax.
- Analysis of neuronal apoptosis and disease severity in infected mice.
- Assessment of Bax-deficient mice for susceptibility to Sindbis virus.
- Studies on cultured hippocampal and dorsal root ganglia neurons.
Main Results:
- Bax expression protected newborn mice from Sindbis virus-induced neuronal apoptosis and mortality.
- Deletion of Bax's N-terminus reversed its function, making it pro-apoptotic in vivo.
- Bax-deficient mice showed increased sensitivity to fatal Sindbis virus infection.
- Bax conferred protection in hippocampal neurons but not dorsal root ganglia neurons.
Conclusions:
- Bax functions as a potent inhibitor of neuronal cell death in the context of Sindbis virus infection.
- Endogenous Bax acts as a survival factor, contributing to age-dependent resistance to viral encephalitis.
- The pro- or anti-apoptotic function of Bax is cell-type specific, influenced by cellular factors.
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