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miR-1303 regulates BBB permeability and promotes CNS lesions following CA16 infections by directly targeting MMP9.

Abstract：

:Coxsackievirus A16 (CA16) is a member of the Picornaviridae family and causes mild and self-limiting hand, foot, and mouth disease (HFMD) in infants and young children. CA16 infection can also progress to central nervous system (CNS) complications; however, the underlying mechanism by which CA16 penetrates the blood-brain barrier (BBB) and then causes CNS damage remains unclear. This study aimed to explore the mechanism of CA16 neurotropic tropism by establishing an in vitro BBB model with CA16 infection and an in vivo CA16 rhesus monkey infant infection model. The results showed that CA16 infection induced increased permeability of the BBB accompanied by upregulation of matrix metalloproteinase 9 (MMP9) expression. Subsequently, high-throughput miRNA sequencing technology and bioinformatics analysis revealed that miR-1303 may regulate BBB permeability by targeting MMP9. Next, we used dual-luciferase, qRT-PCR, and western blot assays to provide evidence of MMP9 targeting by miR-1303. Further experiments revealed that CA16 infection promoted the degradation of junctional complexes (Claudin4, Claudin5, VE-Cadherin, and ZO-1), likely by downregulating miR-1303 and upregulating MMP9. Finally, EGFP-CA16 infection could enter the CNS by facilitating the degradation of junctional complexes, eventually causing neuroinflammation and injury to the CNS, which was confirmed using the in vivo rhesus monkey model. Our results indicate that CA16 might penetrate the BBB and then enter the CNS by downregulating miR-1303, which disrupts junctional complexes by directly regulating MMP9 and ultimately causing pathological CNS changes. These results provide new therapeutic targets in HFMD patients following CA16 infection.

journal_name

Emerg Microbes Infect

journal_title

Emerging microbes & infections

authors

Song J,Hu Y,Li H,Huang X,Zheng H,Hu Y,Wang J,Jiang X,Li J,Yang Z,Fan H,Guo L,Shi H,He Z,Yang F,Wang X,Dong S,Li Q,Liu L

doi

10.1038/s41426-018-0157-3

subject

Has Abstract

pub_date

2018-09-19 00:00:00

pages

155

issue

issn

2222-1751

pii

10.1038/s41426-018-0157-3

journal_volume

pub_type

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miR-1303 regulates BBB permeability and promotes CNS lesions following CA16 infections by directly targeting MMP9.