Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection.
Authors: Kehn-Hall Kylene, Narayanan Aarthi, Lundberg Lindsay, Sampey Gavin, Pinkham Chelsea, Guendel Irene, Van Duyne Rachel, Senina Svetlana, Schultz Kimberly L, Stavale Eric, Aman M Javad, Bailey Charles, Kashanchi Fatah
Journal: PloS one
Summary
# Venezuelan Equine Encephalitis Virus: A Cellular Target for Neuroprotection Venezuelan equine encephalitis virus (VEEV) causes severe, often fatal encephalitis in both horses and humans by triggering excessive pro-inflammatory immune responses within hours of infection, yet the host mechanisms underlying this pathology remain incompletely understood. Kehn-Hall and colleagues investigated glycogen synthase kinase-3 beta (GSK-3β)—a cellular protein implicated in inflammation and neurodegeneration—as a potential therapeutic target, testing GSK-3β inhibitors in both cultured cells and mouse models of VEEV infection. The researchers identified a compound called BIOder as a particularly potent GSK-3β inhibitor (IC₅₀ ~0.5 µM), which demonstrated superior activity compared to existing inhibitors and shifted infected cells toward an anti-apoptotic state by increasing survivin whilst decreasing pro-apoptotic gene expression. Importantly, BIOder treatment provided partial protection against VEEV-induced mortality in infected mice, suggesting that modulating GSK-3β activity could represent a viable strategy to limit the neuroinflammatory cascade underlying encephalitic complications. For equine practitioners managing VEEV cases or considering preventive approaches in at-risk populations, these findings highlight a novel therapeutic avenue that may reduce encephalitis severity and mortality by dampening the host's own inflammatory response rather than targeting the virus directly—a distinction that could prove valuable given the rapid viral adaptation and limited antiviral options currently available.
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Practical Takeaways
- •GSK-3β inhibitors may represent a novel therapeutic approach for managing Venezuelan equine encephalitis in affected horses and humans, though further development is needed
- •The neuroprotective mechanism appears to involve modulation of apoptotic pathways rather than direct viral suppression alone
- •This research is foundational and not yet clinically applicable; further in vivo studies and safety testing would be required before veterinary use
Key Findings
- •GSK-3β inhibition reduced VEEV replication in vitro with the compound BIOder showing IC50 of ~0.5 μM and CC50 >100 μM
- •VEEV infection altered GSK-3β complex formation from one complex in uninfected cells to three distinct complexes
- •BIOder treatment increased anti-apoptotic gene survivin and decreased pro-apoptotic gene BID expression
- •BIOder provided partial protection against VEEV-induced mortality in mice