Long-term, West Nile virus-induced neurological changes: A comparison of patients and rodent models

Abstract

West Nile virus (WNV) is a mosquito-borne virus that can cause severe neurological disease in those infected. Those surviving infection often present with long-lasting neurological changes that can severely impede their lives. The most common reported symptoms are depression, memory loss, and motor dysfunction. These sequelae can persist for the rest of the patients' lives. The pathogenesis behind these changes is still being determined. Here, we summarize current findings in human cases and rodent models, and discuss how these findings indicate that WNV induces a state in the brain similar neurodegenerative diseases. Rodent models have shown that infection leads to persistent virus and inflammation. Initial infection in the hippocampus leads to neuronal dysfunction, synapse elimination, and astrocytosis, all of which contribute to memory loss, mimicking findings in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). WNV infection acts on pathways, such as ubiquitin-signaled protein degradation, and induces the production of molecules, including IL-1β, IFN-γ, and α-synuclein, that are associated with neurodegenerative diseases. These findings indicate that WNV induces neurological damage through similar mechanisms as neurodegenerative diseases, and that pursuing research into the similarities will help advance our understanding of the pathogenesis of WNV-induced neurological sequelae.

Keywords: Behavioral model; Cognition; Inflammation; Neuroinflammation; Virus; WNV; West Nile virus.

Fig. 1

Long-term, WNV-induced changes in the brain compared to ND. Both WNV infection (left) and neurodegenerative disease (right) are associated with long-term inflammation leading to neuronal damage and dysfunction. Infiltrating T cells activate microglia through IFN-γ signaling. In ND, T cells and IFN-γ have been shown to be directly neurotoxic. In both cases, activated microglia proliferate and form nodules. The activated microglia phagocytose presynaptic terminals that are marked with C1q, and C3 in the case of ND. This causes neurological deficits including memory loss. In ND, activated microglia produce pro-inflammatory cytokines including TNF-α, which activates astrocytes. In WNV and ND, astrocytes are signaled to become A1 astrocytes, which produce active IL-1β, stimulating astrocytosis and decreased neurogenesis in the hippocampus. Lipocalin-2 is upregulated in the brain in both cases, and this has been shown to come from A1 astrocytes in ND. Astrocyte-derived lipocalin-2 is neurotoxic in ND. Both WNV and ND induce the accumulation of misfolded proteins in neurons, inducing neuronal dysfunction and apoptosis. α-synuclein is upregulated in both ND and WNV infection. In ND this has been shown to cause neuronal apoptosis and decreased neurogenesis from neural stem cells.