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Heather M. Berens, Ph.D.

Tyler Lab


Complete Title of Thesis:

"The Bcl-2 Family Proteins Bax and Bak Play Important But Separate Roles In the Pathogenesis of Reovirus Encephalitis"

Prepared under the direction of: Kenneth L. Tyler, M.D.


Reovirus encephalitis is a classic experimental model system for studying viral infections of the central nervous system (CNS). Type 3 reovirus strains induce apoptosis, a form of programmed cell death, in infected cells including neurons in the CNS during encephalitis. The intrinsic pathway of apoptosis is regulated by the Bcl-2 family proteins, and it was found that during reovirus infection the executioner proteins Bax and Bak are both activated in infected neurons in vitro and in vivo. Additionally, Bak activation was also found in astrocytes in vivo during encephalitis. To address the importance of Bax and Bak in reovirus encephalitis, transgenic mice with mutations in Bax or Bak were infected with type 3 reoviruses. Reovirus infected Bax-deficient mice survived significantly longer than wild type (WT) control mice. Virally mediated tissue injury and apoptosis was significantly decreased in Bax-deficient mice compared to WT mice. Viral growth was also restricted in the brain, but transneuronal transport of the virus was not impaired in the absence of Bax. Bax was shown to be important for release of the mitochondrial proteins cytochrome c and Smac in infected neurons, however it was not absolutely required. Using a reovirus strain that also causes myocarditis, it was found that Bax was not required for viral growth, tissue injury, cytochrome c release, or apoptosis in the heart. These results are in contrast to those seen in the brain, suggesting that the role of Bax in reovirus pathogenesis is organ specific. Bak-deficient mice also showed a significant increase in survival during reovirus encephalitis in comparison to WT control mice. There was a significant decrease in tissue injury in Bak-deficient mice at late points in disease compared to WT controls. However, there was no difference seen in viral growth, release of cytochrome c and Smac, or apoptosis in the brains of Bak-deficient mice. Bak-deficient hearts also showed no difference from WT hearts in viral growth or apoptosis. Thus, Bax-mediated release of cytochrome c and Smac from the mitochondria contributes to the pathogenesis of reovirus encephalitis, but Bak contributes to pathogenesis in a manner differing from Bax.