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.