2. Academic Validation
  3. MFSD6 is an entry receptor for enterovirus D68

MFSD6 is an entry receptor for enterovirus D68

  • Nature. 2025 May;641(8065):1268-1275. doi: 10.1038/s41586-025-08908-0.
Lauren Varanese # 1,  Lily Xu # 1,  Christine E Peters 1,  Grigore Pintilie 2,  David S Roberts 3 4,  Suyash Raj 5,  Mengying Liu 6,  Yaw Shin Ooi 7,  Jonathan Diep 1,  Wenjie Qiao 1,  Christopher M Richards 1,  Jeremy Callaway 5,  Carolyn R Bertozzi 3 4 8,  Sabrina Jabs 9,  Erik de Vries 6,  Frank J M van Kuppeveld 6,  Claude M Nagamine 10,  Wah Chiu 11 12 13,  Jan E Carette 14
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2 Department of Bioengineering, Stanford University, Stanford, CA, USA.
  • 3 Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • 4 Department of Chemistry, Stanford University, Stanford, CA, USA.
  • 5 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • 6 Virology Group, Division of Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
  • 7 Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
  • 8 Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
  • 9 Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • 10 Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • 11 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. wahc@stanford.edu.
  • 12 Department of Bioengineering, Stanford University, Stanford, CA, USA. wahc@stanford.edu.
  • 13 Division of CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA, USA. wahc@stanford.edu.
  • 14 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. carette@stanford.edu.
  • # Contributed equally.
PMID: 40132641 DOI: 10.1038/s41586-025-08908-0
Abstract

With the near eradication of poliovirus due to global vaccination campaigns, attention has shifted to Other enteroviruses that can cause polio-like paralysis syndrome (now termed acute flaccid myelitis)1-3. In particular, Enterovirus D68 (EV-D68) is believed to be the main driver of epidemic outbreaks of acute flaccid myelitis in recent years4, yet not much is known about EV-D68 host interactions. EV-D68 is a respiratory virus5 but, in rare cases, can spread to the central nervous system to cause severe neuropathogenesis. Here we use genome-scale CRISPR screens to identify the poorly characterized multipass membrane transporter MFSD6 as a host entry factor for EV-D68. Knockout of MFSD6 expression abrogated EV-D68 Infection in cell lines and primary cells corresponding to respiratory and neural cells. MFSD6 localized to the plasma membrane and was required for viral entry into host cells. MFSD6 bound directly to EV-D68 particles through its extracellular, third loop (L3). We determined the cryo-electron microscopy structure of EV-D68 in a complex with MFSD6 L3, revealing the interaction interface. A decoy receptor, engineered by fusing MFSD6 L3 to Fc, blocked EV-D68 Infection of human primary lung epithelial cells and provided near-complete protection in a lethal mouse model of EV-D68 Infection. Collectively, our results reveal MFSD6 as an entry receptor for EV-D68, and support the targeting of MFSD6 as a potential mechanism to combat infections by this emerging pathogen with pandemic potential.

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