West Nile virus (WNV) and Japanese encephalitis virus (JEV) are major mosquito-borne pathogens that cause severe neurological illnesses in humans, including encephalitis and meningitis. Neurons are the primary target of WNV and JEV infections in the brain. However, the pathogenic mechanisms and host immune response associated with WNV and JEV infections in the primary neurons are not fully characterized. Herein, using high-throughput RNA sequencing (RNA-Seq), we performed a comparative transcriptomic analysis of the primary mouse neurons following infection with WNV and JEV. We identified differentially expressed host genes (DEGs) that were commonly induced in neurons by both viruses, as well as those uniquely regulated in a virus-specific manner. We observed pronounced changes in gene expression profiles that indicate activation of a robust antiviral response accompanied by signatures of neuronal dysfunction. Notably, interferon-stimulated genes such as Irf7, Isg15, and Ifnb1 were markedly upregulated in WNV- and JEV-infected neurons. Additionally, we observed the significant upregulation of proinflammatory chemokine and cytokine genes such as Il6, Cxcl2 and Cxcl10 which was further validated by Luminex assay. Ingenuity Pathway Analysis (IPA) revealed the activation of several cell death pathways including pyroptosis and necroptosis. We also showed the significant dysregulation in pattern recognition receptors and neurotransmitter receptors such as glutamatergic and acetylcholine receptors. This dysregulation extended to the synaptic signaling and reduced synaptogenesis in infected neurons. Quantitative RT-PCR confirmed the upregulation of key cytokines like Il6 and Ifna, further establishing the validity of the RNA-Seq approach. Overall, this study provides insights into the pathological changes in the neurons following WNV and JEV infections.
Elsharkawy et al. (Wed,) studied this question.