Regulation of host responses and viral replication by the mitogen-activated protein kinases in intestinal epithelial cells infected with Enterovirus 71

•Enterovirus 71 (EV71) is an important neurotropic enterovirus in children.•Mechanisms of host responses were explored to understand how they are regulated in EV71-infected intestinal epithelial cells.•EV71 viral replication and host responses were regulated by MAP kinase and NF-κB signaling in intestinal epithelial cells.

Enterovirus 71 (EV71) has become an important neurotropic enterovirus in children since the eradication of the poliovirus. A cytokine storm with elevated levels of proinflammatory cytokines is proposed as critical to the pathogenesis of EV71-induced brain stem encephalitis with pulmonary edema, often a fatal complication. Mitogen-activated protein kinases (MAPK) are involved in cellular processes including immune responses and apoptosis. EV71 infection can trigger MAPK activation in human cells, and extracellular signal-regulated kinase (ERK) signaling is essential for EV71 replication. In this study, we report that in EV71-infected human intestinal epithelial cells (HT-29), both ERK1/2 and Jun-N-terminal kinase 1/2 (JNK1/2) were phosphorylated and activated. While MAPK was not involved in the induction of IL-1β, the expressions of IL-6 and IL-8 were positively regulated by both ERK1/2 and JNK1/2, which were also responsible for type I IFN induction. HT-29 cells underwent apoptosis in EV71 infection, but the activation of ERK1/2 and JNK1/2 signaling appeared to suppress induction of TNF-α and FasL and inhibit extrinsic apoptosis in infected cells. Activation of NF-κB was also observed in HT-29 cells in EV71 infection, leading to increased viral replication and proinflammatory cytokine induction. However, the activation of NF-κB was inhibited by the inhibitors of ERK1/2, p38 and JNK1/2, indicating that a cross-talk may exist between MAPK and NF-κB pathways in EV71-infected intestinal epithelial cells. Understanding host responses and their underlying mechanisms may help develop effective therapeutics against EV71 and tools for control of future EV71 outbreaks.