Venezuelan equine encephalitis virus infection causes chronic neurobehavioral outcomes, cellular remodeling, and hippocampal single-cell transcriptomic changes.

Venezuelan equine encephalitis virus (VEEV), a neuroinvasive alphavirus, can cause significant neurological deficits in humans. Viral infections, including VEEV, have been linked to neurological diseases such as Parkinson's and Alzheimer's, though mechanisms remain unclear. Currently, not only are there no therapeutic options for VEEV available, but there is also limited information on the host responses following infection that contribute to neurological sequelae. To fill this gap in knowledge, longitudinal neuropathological, behavioral, and single-cell transcriptomic changes were examined in C57BL/6 mice intranasally infected with VEEV TC-83. Acute infection significantly altered inflammatory and innate immune single-cell signaling, induced astrocyte and microglia activation, and resulted in the loss of neurons in the hippocampus. Persistent motor dysfunction, memory impairment, and reduced anxiety-like behavior were observed up to 106 days post-infection (DPI) and more significantly in animals that displayed neurological symptoms during acute infection. These changes correlated with alterations in single-cell gene expression of synaptogenic signaling genes, neuron loss, and persistent glia cell activation at 106 DPI. Collectively, this study demonstrates that infection with VEEV induces chronic alterations in the hippocampus that correlate with neurological sequelae observed in human patients.