Research Interests

Our laboratory uses reoviruses as an experimental model system to understand how discrete viral genes and the proteins they encode determine the capacity of viruses to produce disease and cellular injury. A major focus of our laboratory has been in the area of virus-induced apoptosis. We have recently shown that reoviruses can induce apoptosis both in vitro and in vivo, and that reovirus strains can differ in this capacity. Studies currently underway include:

1. Signal transduction in reovirus-induced apoptosis.
• Reovirus-induced regulation of the transcription factor nuclear factor kappa B (NF-kB) is required for the apoptotic cell death of virus-infected cells. Reovirus-induced apoptosis thus requires both an early phase of activation and a later phase where the activation of NF-kB is blocked.
• Activation of both c-Jun N-terminal kinase (JNK) and that c-Jun transcription factor are also associated with reovirus-induced cell death.
• Reovirus-induced apoptosis is mediated by TNF-related apoptosis inducing ligand (TRAIL), which binds to cell surface death receptors DR4 and DR5 resulting in the FADD-dependent activation of cellular caspases. Reovirus can sensitize cells, including cell lines derived from a variety of human cancers, to TRAIL-induced apoptosis by a mechanism that involves an increase in the activation of caspase 8.
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2. Mechanisms of viral pathogenesis and development of anti-viral therapies,
• Focus on role of virus-induced apoptosis using in vitro and in vivo models of viral myocarditis, encephalitis, and hepatitis.
• Genomic and Proteomic approaches to the delineation of signal transduction pathways essential for viral pathogenesis
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3. Virus-induced neuronal apoptosis in mouse CNS and primary neuronal cultures.
• Reovirus-induced neuronal apoptosis is mediated by death receptor (DR) signaling. Intrinsic mitochondria-mediated pro-apoptotic signaling is necessary to amplify pro-apoptotic signals initiated by DR's. Mitochondrial death signals are mediated by BH3 only Bcl-2 family proteins Bid, Bax, and Bim and result in smac release from the mitochondria. Smac-mediated inhibition of IAP family proteins is nessecary to activate caspase 3 and execute virus-induced neuronal apotosis.
• Caspase inhibition protect neurons from reovirus-induced apoptosis; in vitro and in vivo.
• The capacity to induce apoptosis may be associated with neurovirulence: studies comparing CNS injury and apoptosis by a highly neurovirulent reovirus with that of an attenuated strain.
• Virus-induced CNS apoptosis plays a role in human viral infection of the CNS, specifically in HSV encephalitis, congenital CMV encephalitis, and HIV and non-HIV associated PML.
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4. Pathways of reovirus induced cell death in neural systems.
• The role of reactive oxygen species and excititoxic pathways.
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5. The role of reovirus nonstructural protein sigma1small in viral pathogenesis.
• sigma1small subcellular localization
• comparison of viral pathogenesis in mice infected with either wild-type reovirus or sigma1small-null reovirus.
• Analysis of protein-protein interactions between sigma1small and host cell proteins using yeast2hybrid, immunoprecipitation and immunoflourescence.
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