Sex differences in neurocognitive recovery from West Nile virus neuroinvasive disease

Viruses that infect the brain raise the risk of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. West Nile virus, the leading cause of mosquito-borne brain infections in North America, causes a self-limited febrile illness or brain infection, also known as encephalitis, which has a survival rate of 90%. However, 40-70% of human survivors of WNV-induced encephalitis exhibit memory impairments that worsen over time. Recently, WNV infection has been linked to increased brain expression of a protein called alpha-synuclein, which have been shown to control and clear virus in the brain. Of interest, Parkinson-like diseases, characterized by accumulation of 'misfolded' alpha-synuclein, may be caused by WNV encephalitis, inducing significant cognitive impairments. Misfolded proteins are believed to be at the core of neurodegenerative diseases. Many neurodegenerative diseases exhibit sex differences in prevalence, incidence, and/or severity; males are more likely to develop those associated with alpha-synuclein. Our studies in mice reveal males exhibit significantly worse cognitive recovery than females after WNV infection with disruption of neuronal networks in the hippocampus, a brain region essential for learning and memory. Preliminary examination of genes expressed by cells from the brains of female vs. male mice after WNV infection shower higher expression of genes that induce misfolded protein responses. We also observed sex differences in genes that regulate gene expression in a sex-specific fashion. Based on these results, we hypothesize that sex differences in cognitive recovery arise from sex-dependent mechanisms that influence the accumulation and clearance of misfolded proteins. We will test this hypothesis by examining whether genes that cause protein misfolding or differently change gene expression depending on sex are essential for memory and learning impairments in female and male mice infected with WNV.