Zika Virus Infection Is More Highly Replicative and Transmissible by Extracellular Vesicles in Human than in Mouse Neuronal Cells

ZIKA virus (ZIKV) infections in human neonates and adults are associated with deleterious effects on brain cognition and neurological disorders. The mechanism(s) of ZIKV infection in neurons and associated neuronal antiviral responses are not fully understood. In this study, we determined the effects of ZIKV infectivity in human neuronal (SH-SY5Y) cells and mouse N2a cells/primary cultures of murine cortical neurons at early and late tested timepoints of infection. The human neuronal cells had higher ZIKV loads compared to the mouse N2a cells, but the viral loads in the murine cortical neurons were between the loads in these two in vitro cell lines. The murine cortical neurons were thought to be more permissive to ZIKV infection, but viral infection kinetics showed a declining trend like that observed in the mouse N2a cells. We noted that infectious extracellular vesicle (EV)-mediated ZIKV infection showed higher viral loads in the SH-SY5Y cells compared to direct infection with laboratory virus stocks. Similar results were obtained with ZIKV infectious EVs in the mouse N2a cells and cortical neurons. In addition, we noted that ZIKV infection significantly induced EV secretion from all three neuronal cells. Also, we found that ZIKV infection modulates the expression of type 1 interferons (IFNs) and entry receptors such as Tyro3, Axl, and MER-TK (TAM). Alongside the increased ZIKV loads in the SH-SY5Y cells, IFN-beta transcript levels and receptors Tyro3/MER-TK were upregulated at early timepoints of infection. Overall, the reduced ZIKV loads and decreasing IFN expression in the mouse neuronal cells suggested a unique murine cellular ability to restrict and limit viral replication. This could be one of the reasons for the unavailability of wild-type mouse models for ZIKV infection. Our data further shows that ZIKV may preferentially infect human rather than murine neuronal cells, and this could be the potential reason for microcephaly in newborns.