Tunicamycin enhances neuroinvasion and encephalitis in mice infected with Venezuelan equine encephalitis virus.
Authors: Steele K E, Seth P, Catlin-Lebaron K M K, Schoneboom B A, Husain M M, Grieder F, Maheshwari R K
Journal: Veterinary pathology
Summary
Venezuelan equine encephalitis (VEE) poses a genuine threat to equine and human populations, yet little has been known about factors that might increase susceptibility to neuroinvasive disease. Researchers at this institution exposed CD-1 mice to tunicamycin—a protein glycosylation inhibitor—before infecting them with virulent or attenuated VEE strains, then tracked viral load in the brain, systemic circulation, and survival times. Tunicamycin-treated mice showed dramatically elevated brain viral titres (>1,000-fold for virulent V3000 strain) without changes to peripheral viremia, suggesting the compound specifically enhanced neuroinvasion; intriguingly, the virus appeared to breach the central nervous system via the olfactory epithelium rather than through tunicamycin-induced blood-brain barrier damage. Clinical disease was substantially more severe in treated animals, with earlier onset of neurological signs, increased neuronal necrosis and apoptosis, and median survival reduced from 9.9 to 7.3 days. These findings carry important implications for equine practice: animals ingesting structurally similar toxins—notably those from annual ryegrass toxicity—may face heightened vulnerability to encephalitis viruses, warranting increased vigilance during concurrent toxic exposure and VEE risk periods, whilst the olfactory route of neuroinvasion suggests novel targets for understanding and potentially preventing disease progression in susceptible animals.
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Practical Takeaways
- •Horses or livestock exposed to mycotoxins or agents similar to tunicamycin (such as ryegrass toxicity) may face significantly increased risk of severe encephalitis if infected with VEE virus
- •VEE neuroinvasion can occur through olfactory routes independent of systemic viral load, suggesting infection control measures should consider respiratory exposure pathways
- •Monitor for earlier and more severe neurological signs in animals with concurrent exposure to neurotoxic agents and VEE infection
Key Findings
- •Tunicamycin treatment increased brain viral load >1,000-fold for virulent VEE strain V3000 and >100-fold for attenuated strain V3034 in mice 48 hours post-infection
- •Tunicamycin did not alter viremia profiles or viral replication in brain tissue, suggesting enhanced neuroinvasion via olfactory pathway rather than blood-brain barrier breakdown
- •Tunicamycin-treated, VEE-infected mice showed earlier neurological signs, increased neuronal necrosis and apoptosis, with reduced mean survival time (7.3 vs 9.9 days)
- •Exposure to tunicamycin-like toxins (e.g., annual ryegrass toxicity) may increase susceptibility to VEE encephalitis in livestock and horses