Enterovirus 71 infection caused neuronal cell death and cytokine expression in cultured rat neural cells.

Abstract

Fatal enterovirus type-71 (EV71) cases are associated with central nervous system infection characterized by inflammatory cell infiltration and activation, cytokine overproduction, and neuronal cell death. Although EV71 antigen has been detected in neurons and glia, the molecular mechanisms underlying EV71-associated neuroinflammation and neuronal cell death are not fully understood. Using cultured rodent neural cell models, we found that EV71 infection preferentially caused cell death in neurons but not brain-resident immune cells astrocytes and microglia. Neurons, astrocytes, and microglia responded to EV71 infection by releasing distinct profiles of cytokines, including nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, regulated on activation normal T cell expressed and secreted (RANTES), and glutamate. EV71 infection-induced neuronal cell death correlated well with the elevated production of NO, TNF-α, IL-1β, and glutamate as well as activation of microglia. Exogenous addition studies further demonstrated the neurotoxic potential of NO, TNF-α, IL-1β, and glutamate. EV71 infection-induced cytokine expression was accompanied by activation of protein tyrosine phosphorylation, mitogen-activated protein kinases (MAPKs), and NF-κB. Intriguingly, EV71 susceptibility was accompanied by infection-elevated neuronal human scavenger receptor class B member 2 expression in cultured neural cells with age-dependent manner. Biochemical and pharmacological studies revealed that after EV71 infection, microglia and accompanied cytokines play an active role in triggering bystander damage to neurons involving the tyrosine kinase/MAPKs/NF-κB signaling cascade. These data suggest that bystander damage caused by activated glia particularly the microglia could be an alternative mechanism of EV71-associated neuronal cell death. However, its clinical importance and implication require further investigation.