Enterovirus A71 exploits peripheral circulating extracellular vesicles to facilitate blood-brain barrier permeability

This is the authors' abstract. We don't add key points for this paper.

Enterovirus A71 infection can cause hand, foot, and mouth disease to occasionally develop the severe neurological complications, but how peripheral Enterovirus A71 infection affects the blood-brain barrier remains incompletely understood. Here, we show that Enterovirus A71 infection of peripheral susceptible cells increases the release of extracellular vesicles and promotes the enrichment of microRNA-30 and microRNA-34 within these vesicles. The extracellular vesicle-associated microRNAs suppress Notch1 signaling in human brain microvascular endothelial cells, impair endothelial junctional integrity, and increase blood-brain barrier permeability. Activation of Notch1 signaling restores barrier integrity and reduces viral neuroinvasion in neonatal mice. Clinically, serum extracellular vesicle-associated microRNA-30 and microRNA-34 are elevated in patients with severe Enterovirus A71-associated hand, foot, and mouth disease. Together, our findings identify circulating extracellular vesicles as mediators linking peripheral Enterovirus A71 infection to blood-brain barrier dysfunction and suggest that the microRNA-30/34–Notch1 axis contributes to neurological disease progression during severe Enterovirus A71 infection. EV-A71 can cause severe neurological disease, but how peripheral infection disrupts the blood-brain barrier is unclear. Here, the authors show that circulating EVs carrying miRNA-30/34 suppress Notch1 signaling and increase BBB permeability in HBMECs.