Development of a Mouse Model of NY99 West Nile Virus-Induced Neurological Changes

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Abstract

West Nile virus is a mosquito-borne flavivirus with worldwide distribution that can cause severe neurological disease in those infected. After recovery, as many as 60% of patients report neurological deficits that can persist for the rest of their lives. Some of the most common sequelae are depression, memory loss, motor incoordination, and trouble processing information. Although recent research has studied possible mechanisms behind these sequelae in mouse models, these relied on an attenuated virus inoculated directly into the brain. The studies presented here aimed to reproduce these neurological changes in a mouse model using peripheral inoculation of wild-type virus to mimic human infection more closely. The aims were to determine if this form of infection caused neurological deficits, if there were inflammatory changes after infection, and if the viral RNA persisted in the brain. Mice infected with WNV that were euthanized over one month post-infection tended to perform worse than uninfected mice on memory testing, and had persistent inflammatory lesions and viral RNA in multiple brain regions, though both were most commonly found in the hindbrain. WNV-infected mice also showed significant changes in the levels of pro-inflammatory cytokines in the cortex and hindbrain, indicating persistent changes in these regions. Microgliosis and viral RNA of certain brain regions correlated with changes in behavioral tests investigating depressive-like behavior, sensorimotor gating, and motor learning, though there was no correlation with memory function. These studies show that this mouse model of WNV infection causes long-term changes in the brain that can manifest as behavioral changes, which are in part related to inflammation and persistent viral RNA in the brain.

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Neurovirology, West Nile virus, Behavioral testing, Neuroinflammation, Neurological sequelae
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