Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection.
Alphaviruses, including Venezuelan Equine Encephalitis Virus (VEEV), cause disease in both equine and humans that exhibit overt encephalitis in a significant percentage of cases. Features of the host immune response and tissue-specific responses may contribute to fatal outcomes as well as the develo...
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doaj-a88941b1091b4188b28cdceedc7b71302020-11-25T01:35:16ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0174e3476110.1371/journal.pone.0034761Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection.Kylene Kehn-HallAarthi NarayananLindsay LundbergGavin SampeyChelsea PinkhamIrene GuendelRachel Van DuyneSvetlana SeninaKimberly L SchultzEric StavaleM Javad AmanCharles BaileyFatah KashanchiAlphaviruses, including Venezuelan Equine Encephalitis Virus (VEEV), cause disease in both equine and humans that exhibit overt encephalitis in a significant percentage of cases. Features of the host immune response and tissue-specific responses may contribute to fatal outcomes as well as the development of encephalitis. It has previously been shown that VEEV infection of mice induces transcription of pro-inflammatory cytokines genes (e.g., IFN-γ, IL-6, IL-12, iNOS and TNF-α) within 6 h. GSK-3β is a host protein that is known to modulate pro-inflammatory gene expression and has been a therapeutic target in neurodegenerative disorders such as Alzheimer's. Hence inhibition of GSK-3β in the context of encephalitic viral infections has been useful in a neuroprotective capacity. Small molecule GSK-3β inhibitors and GSK-3β siRNA experiments indicated that GSK-3β was important for VEEV replication. Thirty-eight second generation BIO derivatives were tested and BIOder was found to be the most potent inhibitor, with an IC(50) of ∼0.5 µM and a CC(50) of >100 µM. BIOder was a more potent inhibitor of GSK-3β than BIO, as demonstrated through in vitro kinase assays from uninfected and infected cells. Size exclusion chromatography experiments demonstrated that GSK-3β is found in three distinct complexes in VEEV infected cells, whereas GSK-3β is only present in one complex in uninfected cells. Cells treated with BIOder demonstrated an increase in the anti-apoptotic gene, survivin, and a decrease in the pro-apoptotic gene, BID, suggesting that modulation of pro- and anti-apoptotic genes contributes to the protective effect of BIOder treatment. Finally, BIOder partially protected mice from VEEV induced mortality. Our studies demonstrate the utility of GSK-3β inhibitors for modulating VEEV infection.http://europepmc.org/articles/PMC3319612?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kylene Kehn-Hall Aarthi Narayanan Lindsay Lundberg Gavin Sampey Chelsea Pinkham Irene Guendel Rachel Van Duyne Svetlana Senina Kimberly L Schultz Eric Stavale M Javad Aman Charles Bailey Fatah Kashanchi |
spellingShingle |
Kylene Kehn-Hall Aarthi Narayanan Lindsay Lundberg Gavin Sampey Chelsea Pinkham Irene Guendel Rachel Van Duyne Svetlana Senina Kimberly L Schultz Eric Stavale M Javad Aman Charles Bailey Fatah Kashanchi Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection. PLoS ONE |
author_facet |
Kylene Kehn-Hall Aarthi Narayanan Lindsay Lundberg Gavin Sampey Chelsea Pinkham Irene Guendel Rachel Van Duyne Svetlana Senina Kimberly L Schultz Eric Stavale M Javad Aman Charles Bailey Fatah Kashanchi |
author_sort |
Kylene Kehn-Hall |
title |
Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection. |
title_short |
Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection. |
title_full |
Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection. |
title_fullStr |
Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection. |
title_full_unstemmed |
Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection. |
title_sort |
modulation of gsk-3β activity in venezuelan equine encephalitis virus infection. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
Alphaviruses, including Venezuelan Equine Encephalitis Virus (VEEV), cause disease in both equine and humans that exhibit overt encephalitis in a significant percentage of cases. Features of the host immune response and tissue-specific responses may contribute to fatal outcomes as well as the development of encephalitis. It has previously been shown that VEEV infection of mice induces transcription of pro-inflammatory cytokines genes (e.g., IFN-γ, IL-6, IL-12, iNOS and TNF-α) within 6 h. GSK-3β is a host protein that is known to modulate pro-inflammatory gene expression and has been a therapeutic target in neurodegenerative disorders such as Alzheimer's. Hence inhibition of GSK-3β in the context of encephalitic viral infections has been useful in a neuroprotective capacity. Small molecule GSK-3β inhibitors and GSK-3β siRNA experiments indicated that GSK-3β was important for VEEV replication. Thirty-eight second generation BIO derivatives were tested and BIOder was found to be the most potent inhibitor, with an IC(50) of ∼0.5 µM and a CC(50) of >100 µM. BIOder was a more potent inhibitor of GSK-3β than BIO, as demonstrated through in vitro kinase assays from uninfected and infected cells. Size exclusion chromatography experiments demonstrated that GSK-3β is found in three distinct complexes in VEEV infected cells, whereas GSK-3β is only present in one complex in uninfected cells. Cells treated with BIOder demonstrated an increase in the anti-apoptotic gene, survivin, and a decrease in the pro-apoptotic gene, BID, suggesting that modulation of pro- and anti-apoptotic genes contributes to the protective effect of BIOder treatment. Finally, BIOder partially protected mice from VEEV induced mortality. Our studies demonstrate the utility of GSK-3β inhibitors for modulating VEEV infection. |
url |
http://europepmc.org/articles/PMC3319612?pdf=render |
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