Abstract

Mammalian reoviruses infect cells in the central nervous system (CNS) of newborn mice, leading to apoptosis and lethal encephalitis. Reovirus-induced apoptosis requires engagement of cell-surface receptors, intracellular signaling, and activation of transcription factor NF-kappaB. Experiments are proposed to identify viral and cellular determinants of reovirus-induced apoptosis and elucidate the significance of this host-cell response in vivo. The central hypothesis of the proposed research is that NF-kappaB activation and apoptosis are required for reovirus-induced CNS disease.
In Specific Aim 1, steps in reovirus replication that lead to NF-kappaB activation and apoptosis will be defined.
In Specific Aim 2, intracellular signaling events required for reovirus-induced NF-kappaB activation and apoptosis will be identified.
In Specific Aim 3, the role of NF-kappaB activation and apoptosis in reovirus virulence will be investigated. These experiments will provide an enhanced understanding of how viruses perturb host-cell-signaling pathways to cause cell death and disease. Information gained from these studies should foster development of new antiviral strategies designed to inhibit apoptosis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050080-02
Application #
6511612
Study Section
Virology Study Section (VR)
Program Officer
Meegan, James M
Project Start
2001-09-01
Project End
2006-05-31
Budget Start
2002-07-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$251,038
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212

  Publications

Stebbing, Rachael E; Irvin, Susan C; Rivera-Serrano, Efraín E et al. (2014) An ITAM in a nonenveloped virus regulates activation of NF-?B, induction of beta interferon, and viral spread. J Virol 88:2572-83
Danthi, Pranav; Holm, Geoffrey H; Stehle, Thilo et al. (2013) Reovirus receptors, cell entry, and proapoptotic signaling. Adv Exp Med Biol 790:42-71
Knowlton, Jonathan J; Dermody, Terence S; Holm, Geoffrey H (2012) Apoptosis induced by mammalian reovirus is beta interferon (IFN) independent and enhanced by IFN regulatory factor 3- and NF-ýýB-dependent expression of Noxa. J Virol 86:1650-60
Sen, Adrish; Pruijssers, Andrea J; Dermody, Terence S et al. (2011) The early interferon response to rotavirus is regulated by PKR and depends on MAVS/IPS-1, RIG-I, MDA-5, and IRF3. J Virol 85:3717-32
Boehme, Karl W; Ikizler, Mine; Kobayashi, Takeshi et al. (2011) Reverse genetics for mammalian reovirus. Methods 55:109-13
Holm, Geoffrey H; Pruijssers, Andrea J; Li, Lianna et al. (2010) Interferon regulatory factor 3 attenuates reovirus myocarditis and contributes to viral clearance. J Virol 84:6900-8
Danthi, Pranav; Pruijssers, Andrea J; Berger, Angela K et al. (2010) Bid regulates the pathogenesis of neurotropic reovirus. PLoS Pathog 6:e1000980
Danthi, Pranav; Guglielmi, Kristen M; Kirchner, Eva et al. (2010) From touchdown to transcription: the reovirus cell entry pathway. Curr Top Microbiol Immunol 343:91-119
Zurney, Jennifer; Kobayashi, Takeshi; Holm, Geoffrey H et al. (2009) Reovirus mu2 protein inhibits interferon signaling through a novel mechanism involving nuclear accumulation of interferon regulatory factor 9. J Virol 83:2178-87
Danthi, Pranav; Coffey, Caroline M; Parker, John S L et al. (2008) Independent regulation of reovirus membrane penetration and apoptosis by the mu1 phi domain. PLoS Pathog 4:e1000248

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