Hippocampal single cell transcriptomic changes and cellular remodeling is associated with chronic neurobehavioral outcomes following alphavirus infection

Viral infections, including Venezuelan equine encephalitis virus (VEEV), have been likened to neurological diseases such as Parkinson’s and Alzheimer’s, though mechanisms remain unclear. VEEV, a neuroinvasive alphavirus, can cause significant neurological deficits in humans. Chronic effects of VEEV are poorly understood, with no antivirals or neuroprotective treatments available. This study examines longitudinal neuropathological, behavioral, and single-cell transcriptomic changes in C57BL/6 mice intranasally infected with VEEV TC-83. Acute infection significantly altered inflammatory and innate immune signaling and induced astrocyte and microglia activation and 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). These changes correlated with alterations in synaptogenic signaling gene expression, 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 may correlate with neurological sequalae observed in human patients.