The role of IKKβ in Venezuelan equine encephalitis virus infection.
Authors: Amaya Moushimi, Voss Kelsey, Sampey Gavin, Senina Svetlana, de la Fuente Cynthia, Mueller Claudius, Calvert Valerie, Kehn-Hall Kylene, Carpenter Calvin, Kashanchi Fatah, Bailey Charles, Mogelsvang Soren, Petricoin Emanuel, Narayanan Aarthi
Journal: PloS one
Summary
# Editorial Summary: IKK-β and Venezuelan Equine Encephalitis Virus Replication Venezuelan equine encephalitis virus (VEEV) is an alphavirus that triggers severe inflammatory responses in infected horses and humans, with evidence suggesting the NF-κB signalling cascade—a key immune pathway—plays a central role in disease pathology. Moushimi and colleagues investigated whether IKK-β, a kinase component upstream in this cascade, undergoes structural reorganisation during VEEV infection and whether blocking its function could reduce viral replication, using both in vitro cell culture systems (TC-83 attenuated and virulent strains) and in vivo mouse models. Treatment with three different IKK-β inhibitors (BAY-11-7082, BAY-11-7085, and IKK2 compound IV) significantly reduced infectious viral particle production and viral RNA copy numbers, whilst overexpression of IKK-β increased viral titres and IKK-β knockout cells showed decreased replication, demonstrating a critical requirement for this protein in the virus lifecycle. Importantly, inhibitor treatment improved survival rates in infected mice, suggesting therapeutic potential, and proteomics analysis identified a direct interaction between IKK-β and the viral non-structural protein nsP3. For equine practitioners, these findings highlight the host immune machinery hijacked by VEEV and point towards potential antiviral strategies targeting IKK-β signalling—an approach distinct from conventional vaccines—though translation to equine therapeutics would require further investigation.
Read the full abstract on PubMed
Practical Takeaways
- •IKK-β is a critical host factor required for VEEV replication and may represent a therapeutic target for treating Venezuelan equine encephalitis in infected horses
- •Small molecule inhibitors of IKK-β function show promise for reducing viral replication and improving survival outcomes in VEEV infection models
- •The NF-κB signaling pathway, particularly IKK-β, represents a potential intervention point for managing VEEV-related inflammation and disease progression
Key Findings
- •IKK-β undergoes macromolecular reorganization to form lower molecular weight complexes during VEEV infection
- •IKK-β inhibitors (BAY-11-7082, BAY-11-7085, IKK2 compound IV) decreased infectious viral particles and viral RNA copies in both attenuated and virulent VEEV strains
- •IKK-β overexpression increased viral titers while IKK-β knockout cells showed decreased VEEV replication
- •IKK-β inhibitor treatment increased survival in TC-83 infected mice in vivo