Sindbis virus is an alphavirus that is transmitted by mosquitoes to animal and human hosts in many geographical locations worldwide. Although Sindbis virus is a relatively mild human pathogen, it causes mild to severe encephalitis and mortality in mice, thereby serving as a model for related human encephalitis viruses. We demonstrated that Sindbis virus induces apoptosis of cultured neurons and in neurons of the brain. Furthermore, we found that mammalian Bcl-2 family proteins and other regulators of cell death have a significant impact on the outcome of a Sindbis virus infection. These studies led to unexpected findings for both the cell and the virus. The goals of this proposal are to understand how cellular regulators of programmed cell death alter the response of neurons to Sindbis virus infection, resulting in acute virus induced neuronal death or long-term persistence. By using Sindbis virus as a vector for gene delivery to neurons of the brain, in combination with knockout mice, we propose to determine how pro-apoptotic Bcl-2 family proteins Bax, Bak and BAD alter viral pathogenesis. We suggest that Bax, Bak and BAD decrease neuronal excitability by regulating mitochondrial functions, resulting in the unexpected effect of protecting neurons and mice from Sindbis virus-induced death and excitotoxic damage. The strategy is to explore the role of Bax, Bak and BAD in neuronal excitability (Aim 1), to link the role of Bax and Bak in regulating synaptic activity to their effects on Sindbis virus infections (Aim 2), and to explore new mechanisms by which host factors suppress viral replication and pro-death functions in mature neurons, leading to the establishment of a persistent infection (Aim 3). ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034175-10
Application #
7017072
Study Section
Special Emphasis Panel (ZRG1-IDM-K (90))
Program Officer
Nunn, Michael
Project Start
1999-07-01
Project End
2010-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
10
Fiscal Year
2006
Total Cost
$332,288
Indirect Cost
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Teng, Xinchen; Hardwick, J Marie (2015) Cell death in genome evolution. Semin Cell Dev Biol 39:3-11
Roelofs, Brian A; Hardwick, J Marie (2011) Flying to a halt: Drosophila Aven arrests the cell cycle. Cell Cycle 10:1350-51
Berman, Sarah B; Chen, Ying-bei; Qi, Bing et al. (2009) Bcl-x L increases mitochondrial fission, fusion, and biomass in neurons. J Cell Biol 184:707-19
Cheng, Wen-Chih; Leach, Kelly M; Hardwick, J Marie (2008) Mitochondrial death pathways in yeast and mammalian cells. Biochim Biophys Acta 1783:1272-9
Berman, S B; Pineda, F J; Hardwick, J M (2008) Mitochondrial fission and fusion dynamics: the long and short of it. Cell Death Differ 15:1147-52
Qi, Bing; Hardwick, J Marie (2008) Bcl-2 turns deadly. Nat Chem Biol 4:722-3
Jonas, Elizabeth A; Hardwick, J Marie; Kaczmarek, Leonard K (2005) Actions of BAX on mitochondrial channel activity and on synaptic transmission. Antioxid Redox Signal 7:1092-100
Ivanovska, Iva; Hardwick, J Marie (2005) Viruses activate a genetically conserved cell death pathway in a unicellular organism. J Cell Biol 170:391-9
Seo, So Young; Chen, Ying-Bei; Ivanovska, Iva et al. (2004) BAD is a pro-survival factor prior to activation of its pro-apoptotic function. J Biol Chem 279:42240-9
Jonas, Elizabeth A; Hickman, John A; Chachar, Mushtaque et al. (2004) Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals. Proc Natl Acad Sci U S A 101:13590-5

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