The neurological damage caused by enterovirus 71 infection is associated with hsa_circ_0069335/miR-29b/PMP22 pathway.

Enterovirus 71 (EV71) infection is usually accompanied by neurological damage, which is the leading cause of death in children with hand-foot-mouth disease. In this study, we demonstrated that EV71 infection can cause pathological damage in the nervous system, such as neuronal vacuolar degeneration, shrinkage of some neurons, edema of brain tissues in the hippocampus, and a decreased number of Nissl bodies in the infarction area. Also, EV71 infection caused apparent structural damage to Schwann cells, including a decreased number of cytoplasmic organelles and severe damage of rough endoplasmic reticulum and mitochondria. However, the pathological damage was alleviated with the decrease of EV71 viral load. The cell experiment showed that EV71 infection significantly reduced ATP levels and promoted Schwann cell apoptosis, thus inhibiting cell growth. The extended infection time and the decreased viral load resulted in the gradual improvement of cell growth status. Meanwhile, EV71 inhibited the expression of miR-29b and promoted the expression of PMP22 in a time-dependent manner at both mRNA and protein levels, with the most significant change at 36 h of infection. Subsequently, the expression of miR-29b and PMP22 was gradually restored with the reduction of EV71 viral load. In addition, EV71 regulated the expression of hsa_circ_0069335, which could bind and co-localize with miR-29b. Therefore, EV71 infection can cause significant damage to the nervous system and may be related to hsa_circ_0069335/miR-29b/PMP22 pathway. The present study provides a new therapeutic target for neurological damage induced by EV71 infection.IMPORTANCEEV71 can cause severe neurological damage and even death, but the mechanism remains unclear. In this study, we exhibited the pathological changes of nervous system in EV71 infection and revealed that the damage degree was consistent with the EV71 viral load. From the molecular perspective, EV71 infection up-regulated the PMP22 expression in Schwann cells, which is accompanied by apparent structural damage of Schwann cells and myelin sheaths. Furthermore, EV71 promoted the expression of PMP22 and inhibited the expression of miR-29b in a time-dependent manner, with the most significant change at 36 h of infection. Otherwise, the hsa_circ_0069335, which binds and co-localizes with miR-29b, was also regulated by EV71 infection. The hsa_circ_0069335/miR-29b/PMP22 axis may be a potential molecular mechanism involved in EV71 infection-induced fatal neuronal damage. Drug development targeting this pathway may bring clinical improvement of EV71-infected patients.