MFSD6 is an entry receptor for enterovirus D68.

Area of Science:

• Virology and Molecular Biology
• Neuroscience and Infectious Diseases

Background:

• Global vaccination has reduced poliovirus, shifting focus to other enteroviruses causing acute flaccid myelitis (AFM).
• Enterovirus D68 (EV-D68) is a primary cause of recent AFM outbreaks, but its host interactions remain poorly understood.
• EV-D68 is a respiratory virus that can cause severe central nervous system disease.

Purpose of the Study:

• To identify host factors involved in EV-D68 entry and infection.
• To elucidate the molecular mechanism of EV-D68 interaction with host cells.
• To explore potential therapeutic targets for EV-D68 infection.

Main Methods:

• Genome-scale CRISPR screens were employed to identify host factors for EV-D68.
• CRISPR screens identified MFSD6 as a critical host entry factor.
• Cryo-electron microscopy was used to determine the structural basis of the EV-D68-MFSD6 interaction.

Main Results:

• MFSD6 knockout abrogated EV-D68 infection in respiratory and neural cell types.
• MFSD6 is a plasma membrane protein essential for viral entry, binding directly to EV-D68 via its extracellular loop 3.
• A decoy receptor targeting MFSD6 L3 blocked EV-D68 infection and protected mice in a lethal infection model.

Conclusions:

• MFSD6 acts as a specific entry receptor for EV-D68.
• The interaction interface between MFSD6 L3 and EV-D68 was structurally characterized.
• Targeting MFSD6 presents a promising therapeutic strategy against EV-D68 infections and potential future outbreaks.