Engagement of the innate immune response by viral infection is a critical nexus of disease pathogenesis. Central unanswered questions in viral pathogenesis are how an infected cell is influenced to either enter an antiviral state or undergo apoptosis and the implication of this decision on viral disease mechanisms. Mammalian reoviruses serve as models for studies of viral pathogenesis and are exquisitely suitable for studies of the innate immune response to viral infection. Reoviruses elicit a strong interferon response by activating transcription factors, including IRF-3, which facilitate interferon-beta production. This response modulates reovirus infection and pathogenesis in a tissue-specific manner. However, the initial triggers of signaling cascades leading to transcriptional activation and the mechanisms of interferon-mediated modulation of reovirus infection and disease are not known. We propose to define viral and cellular determinants of IRF-3 activation following reovirus infection and determine the pathological significance of this cellular response.
Two specific aims are proposed. In the first, mechanisms of reovirus-induced IRF-3 activation will be determined. In the second, the role of IRF-3 activation in reovirus apoptosis and virulence in vivo will be determined. Together, these studies will provide new insights into the interface between the innate antiviral response, cell death pathways, and viral disease pathogenesis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI071440-01
Application #
7156063
Study Section
Special Emphasis Panel (ZRG1-F13-P (20))
Program Officer
Cassetti, Cristina
Project Start
2006-09-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$45,976
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
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
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; Kobayashi, Takeshi; Holm, Geoffrey H et al. (2008) Reovirus apoptosis and virulence are regulated by host cell membrane penetration efficiency. J Virol 82:161-72
Kobayashi, Takeshi; Antar, Annukka A R; Boehme, Karl W et al. (2007) A plasmid-based reverse genetics system for animal double-stranded RNA viruses. Cell Host Microbe 1:147-57
Holm, Geoffrey H; Zurney, Jennifer; Tumilasci, Vanessa et al. (2007) Retinoic acid-inducible gene-I and interferon-beta promoter stimulator-1 augment proapoptotic responses following mammalian reovirus infection via interferon regulatory factor-3. J Biol Chem 282:21953-61