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Sindbis virus induces apoptosis through a caspase-dependent, CrmA-sensitive pathway
V E Nava1, A Rosen, M A Veliuona
1Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health, Baltimore, Maryland 21205, USA.
Abstract:
Sindbis virus infection of cultured cells and of neurons in mouse brains leads to programmed cell death exhibiting the classical characteristics of apoptosis. Although the mechanism by which Sindbis virus activates the cell suicide program is not known, we demonstrate here that Sindbis virus activates caspases, a family of death-inducing proteases, resulting in cleavage of several cellular substrates. To study the role of caspases in virus-induced apoptosis, we determined the effects of specific caspase inhibitors on Sindbis virus-induced cell death. CrmA (a serpin from cowpox virus) and zVAD-FMK (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone) inhibited Sindbis virus-induced cell death, suggesting that cellular caspases facilitate apoptosis induced by Sindbis virus. Furthermore, CrmA significantly increased the rate of survival of infected mice. These inhibitors appear to protect cells by inhibiting the cellular death pathway rather than impairing virus replication or by inhibiting the nsP2 and capsid viral proteases. The specificity of CrmA indicates that the Sindbis virus-induced death pathway is similar to that induced by Fas or tumor necrosis factor alpha rather than being like the death pathway induced by DNA damage. Taken together, these data suggest a central role for caspases in Sindbis virus-induced apoptosis.
Insights
Sindbis virus triggers apoptosis, a form of programmed cell death, by activating caspases. Inhibiting these caspases with CrmA or zVAD-FMK protected infected cells and improved survival rates in mice.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Sindbis virus infection induces apoptosis in cultured cells and mouse neurons.
- The precise mechanism of Sindbis virus-mediated apoptosis activation remains unclear.
Purpose of the Study:
- To investigate the role of caspases in Sindbis virus-induced apoptosis.
- To determine if caspase inhibition can protect against Sindbis virus-induced cell death and improve survival.
Main Methods:
- Utilized specific caspase inhibitors, CrmA and zVAD-FMK, to study Sindbis virus-induced cell death.
- Assessed the impact of inhibitors on cell survival in infected cultures and mice.
- Analyzed whether inhibitors affected viral replication or viral proteases.
Main Results:
- Caspase inhibitors CrmA and zVAD-FMK significantly reduced Sindbis virus-induced cell death.
- CrmA treatment markedly increased the survival rate of infected mice.
- Inhibitor efficacy suggests they target the cellular apoptotic pathway, not viral replication or proteases.
Conclusions:
- Cellular caspases play a critical role in mediating Sindbis virus-induced apoptosis.
- The Sindbis virus apoptotic pathway shares similarities with Fas or TNF-alpha-induced death pathways.
- Targeting caspases represents a potential therapeutic strategy against Sindbis virus infection.