Central nervous system (CMS) viral infections result from the capacity of viruses to injure neurons and other non-neuronal cells within the brain and spinal cord. A common mechanism by which a diverse group of neurotropic viruses injure target cells in the CMS is through apoptosis. Despite this fact, little is known about the precise mechanisms and specific cellular pathways leading to virus-induced apoptotic neural cell death. In this proposal we will utilize reovirus infection of primary neuronal cultures and a murine model of reovirus- induced encephalitis to examine the cellular pathways involved in virus-induced neuronal apoptosis. We have previously shown that death receptor apoptotic signaling contributes to reovirus-indced neuronal apoptosis. We hypothesize that both mitochondrial and endoplasmic reticulum cell stress apoptotic signaling pathways are also critical to reovirus-induced neuronal cell death.
In Aim 1 we will determine the role played by endoplasmic reticulum (ER) and cellular-stress (GADD) pathways on reovirus-induced neuronal apoptosis and characterize the factors involved.
In Aim 2 we will determine the role of mitochondria and mitochondrial factors in reovirus-induced apoptosis. Finally, in Aim 3 we will test the effects of manipulating apoptotic pathways on the pathogenesis of reovirus-induced CNS infection in vivo. A key aspect of the proposed studies is the ability to translate results obtained in studies of primary neuronal cultures in vitro, into an in vivo model of CNS viral infection. Reovirus infection was selected for these studies because it is one of the most extensively characterized models of virus-induced apoptosis and offers the advantage of a large pre- existing base of knowledge concerning viral determinants of apoptosis and the cellular pathways involved, as well as an easily accessible in mouse model of CNS apoptosis that allows rapid testing of results obtained in cell culture for their significance on the pathogenesis of CNS viral disease in vivo
|Zhuang, Yonghua; Berens-Norman, Heather M; Leser, J Smith et al. (2016) Mitochondrial p53 Contributes to Reovirus-Induced Neuronal Apoptosis and Central Nervous System Injury in a Mouse Model of Viral Encephalitis. J Virol 90:7684-91|
|Dionne, Kalen R; Tyler, Kenneth L (2013) Slice culture modeling of central nervous system (CNS) viral infection. Methods Mol Biol 1078:97-117|
|Dionne, Kalen R; Galvin, John M; Schittone, Stephanie A et al. (2011) Type I interferon signaling limits reoviral tropism within the brain and prevents lethal systemic infection. J Neurovirol 17:314-26|
|Dionne, Kalen R; Leser, J Smith; Lorenzen, Kristi A et al. (2011) A brain slice culture model of viral encephalitis reveals an innate CNS cytokine response profile and the therapeutic potential of caspase inhibition. Exp Neurol 228:222-31|
|Berens, Heather M; Tyler, Kenneth L (2011) The proapoptotic Bcl-2 protein Bax plays an important role in the pathogenesis of reovirus encephalitis. J Virol 85:3858-71|
|Beckham, J David; Tuttle, Kathryn D; Tyler, Kenneth L (2010) Caspase-3 activation is required for reovirus-induced encephalitis in vivo. J Neurovirol 16:306-17|
|Tyler, Kenneth L; Leser, J Smith; Phang, Tzu L et al. (2010) Gene expression in the brain during reovirus encephalitis. J Neurovirol 16:56-71|
|DeBiasi, Roberta L; Robinson, Bridget A; Leser, J Smith et al. (2010) Critical role for death-receptor mediated apoptotic signaling in viral myocarditis. J Card Fail 16:901-10|
|Tyler, Kenneth L (2009) Emerging viral infections of the central nervous system: part 2. Arch Neurol 66:1065-74|
|Beckham, J David; Tuttle, Kathryn; Tyler, Kenneth L (2009) Reovirus activates transforming growth factor beta and bone morphogenetic protein signaling pathways in the central nervous system that contribute to neuronal survival following infection. J Virol 83:5035-45|
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