Abstract
Despite the availability of vaccines for Japanese encephalitis virus (JEV), the re-emerging virus remains a clinically important pathogen that causes acute encephalitis and permanent neuropsychiatric sequels. JEV highly targets dopaminergic neuron-rich brain regions including the thalamus and midbrain. The molecular mechanism contributing to the high susceptibility of these particular brain regions remains largely unclear. This study addressed whether this tissue tropism of JEV is associated with signaling of dopaminergic neurons. Three pieces of evidence indicate that JEV exploits dopamine signaling to facilitate its infection: (1) JEV infection modulates dopamine level; (2) a selective dopamine D2 receptor (D2R) agonist enhances JEV infection; and (3) stimulation of D2R activates phospholipase C (PLC) to enhance the surface expression of JEV binding/entry molecules, integrin β3 and vimentin. Overall, JEV may exploit dopamine-mediated neuronal communication to increase the susceptibility of D2R-expressing cells to JEV infection. This study identifies a potential underlying mechanism of viral invasiveness in the dopaminergic brain regions and suggests antiviral strategies against viral infection by targeting D2R-PLC signaling.
Highlights
Japanese encephalitis virus (JEV), transmitted by mosquitoes, is the most clinically important etiological agent of viral encephalitis, with an estimated worldwide annual incidence of 30,000 to 50,000 cases
JEV-infected BE(2)C cells released a significantly higher level of dopamine at 3 and 6 h post-infection as compared with mock-infected cells; at later times of 24 and 36 hpi dopamine release was reduced by JEV infection (Figure 1A), probably due to cytopathic effect caused by JEV
We provide evidence to explain this tissue tropism by revealing an interesting approach adapted by JEV to exploit the dopaminergic system to enhance its viral life cycle
Summary
Japanese encephalitis virus (JEV), transmitted by mosquitoes, is the most clinically important etiological agent of viral encephalitis, with an estimated worldwide annual incidence of 30,000 to 50,000 cases. JEV, a flavivirus with positive-sense RNA genome, enters cell by receptor mediated endocytosis and the acidic pH of endosome causes conformational changes in envelope protein leading to release of genome into cytoplasm. Virus assembly is taken place within the endoplasmic reticulum-derived membrane compartments and non-infectious particles traverse through Golgi complex where furin-mediated cleavage of prM leads to conformational changes producing the infectious virion, which are released into extracellular compartment through cellular secretory pathway. JEV invades the central nervous system (CNS) and primarily infects neuronal cells (Unni et al, 2011). In CNS infection, the thalamus and midbrain are the most severely affected
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