Enterovirus D68 (EV-D68) is a leading non-polio enterovirus that causes severe respiratory diseases and poliomyelitis-like illness in children. Viral entry represents a potential multifaceted target for antiviral intervention; however, there are no approved inhibitors to block EV-D68. Here, we identify the functionally undescribed membrane protein major facilitator superfamily-domain-containing protein 6 (MFSD6) as an EV-D68 entry factor amenable to therapeutic intervention. Specifically, MFSD6 expression is crucial for EV-D68 replication. MFSD6 binds to EV-D68 particles and is necessary for virus attachment to cells. The second extracellular domain of the MFSD6 molecule is involved in the recognition of EV-D68. On the basis of these findings, we engineered a recombinant protein complex comprising the MFSD6 ectodomain fused to Fc (MFSD6-Fc(CH3)), which potently inhibited EV-D68 uptake. MFSD6-Fc(CH3) effectively blocked EV-D68 infection in vitro and prevented lethality in newborn mice. In conclusion, our study not only identifies MFSD6 as an EV-D68 entry factor but also reveals a potential antiviral target and therapeutic agent.
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Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
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Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China; Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, Jilin 130021, China; Institute of Translational Medicine, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin 130021, China. Electronic address:
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