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.
Highlights
Introduction CoxsackievirusA16 (CA16), which belongs to the human enterovirus A species of the Picornaviridae family, is one of the major causative agents of hand, foot, and mouth disease (HFMD), which is a common infectious disease mostly seen in children under 5 years old[1]
Proliferation kinetics of Coxsackievirus A16 (CA16) in Human umbilical vein endothelial cells (HUVECs) To assess whether CA16 can infect and proliferate in HUVECs, the cell line was inoculated with each virus and analyzed for proliferation kinetics; EV71 experiments were performed in the same manner as the control
The production of infectious virus particles gradually increased over time with EV71 and CA16 infections (Fig S1B), suggesting that HUVECs are highly susceptible to EV71 and CA16
Summary
Introduction CoxsackievirusA16 (CA16), which belongs to the human enterovirus A species of the Picornaviridae family, is one of the major causative agents of hand, foot, and mouth disease (HFMD), which is a common infectious disease mostly seen in children under 5 years old[1]. Accumulating evidence in recent years has demonstrated that CA16 might be more virulent in children and has induced severe cases of CNS complications and fatal outcomes, which were similar to those of EV71 infections[6]. Some severe and fatal HFMD cases with CA6 and CA10 infections have shown a clear increasing trend in recent years[7]. Taken together, these findings demonstrate that it is important to explore the underlying molecular basis of HFMD pathogenesis and progression induced by CA16 infections, which might provide novel approaches for the development of vaccines that cover multiple species of enterovirus
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
