Journal article
Modulation of GSK-3[beta] Activity in Venezuelan Equine Encephalitis Virus Infection
PloS one, v 7(4), e34761
04 Apr 2012
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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-[gamma], IL-6, IL-12, iNOS and TNF-[alpha]) within 6 h. GSK-3[beta] 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-3[beta] in the context of encephalitic viral infections has been useful in a neuroprotective capacity. Small molecule GSK-3[beta] inhibitors and GSK-3[beta] siRNA experiments indicated that GSK-3[beta] 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.sub.50 of ~0.5 [micro]M and a CC.sub.50 of >100 [micro]M. BIOder was a more potent inhibitor of GSK-3[beta] than BIO, as demonstrated through in vitro kinase assays from uninfected and infected cells. Size exclusion chromatography experiments demonstrated that GSK-3[beta] is found in three distinct complexes in VEEV infected cells, whereas GSK-3[beta] 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-3[beta] inhibitors for modulating VEEV infection.
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Details
- Title
- Modulation of GSK-3[beta] Activity in Venezuelan Equine Encephalitis Virus Infection
- Creators
- Svetlana Senina - George Mason UniversityIrene Guendel - George Mason UniversityAarthi Narayanan - George Mason UniversityChelsea Pinkham - George Mason UniversityLindsay Lundberg - George Mason UniversityKimberly L Schultz - Johns Hopkins UniversityRachel Van Duyne - George Washington UniversityGavin Sampey - George Mason UniversityKylene Kehn-HallM. Javad Aman - Integrated BioTherapeuticsEric Stavale - Integrated BioTherapeuticsFatah Kashanchi - George Mason UniversityCharles Bailey - George Mason University
- Publication Details
- PloS one, v 7(4), e34761
- Publisher
- Public Library of Science
- Number of pages
- 12
- Grant note
- National Institutes of Health (NIH): AI0078859, AI0074410, NS070740
This work was supported by National Institutes of Health (NIH) grants AI0078859, AI0074410 and NS070740 to FK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000304855200078
- Scopus ID
- 2-s2.0-84859369193
- Other Identifier
- 991021902519604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Virology