Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• Human metapneumovirus (hMPV) causes significant respiratory illness in children.
• The hMPV F glycoprotein is crucial for viral entry and a key target for neutralizing antibodies.
• Previous studies were limited by the inability to obtain the F glycoprotein in its pre-fusion conformation.

Purpose of the Study:

• To engineer and determine the crystal structure of a pre-fusion-stabilized hMPV F ectodomain.
• To elucidate the molecular mechanisms of hMPV fusion and antibody interactions.

Main Methods:

• Engineering a stabilized hMPV F ectodomain.
• X-ray crystallography to determine the structure at 2.6 Å resolution.
• Immunological studies including immunoglobulin depletion and mouse immunizations.

Main Results:

• The crystal structure of the pre-fusion hMPV F ectodomain was determined.
• Identified molecular determinants of strain-dependent, acid-induced fusion.
• Revealed insights into the conformational changes from pre- to post-fusion states.
• A dense glycan shield at the apex of pre-fusion hMPV F was observed, potentially hindering antibody recognition.

Conclusions:

• The structural insights provide a foundation for understanding hMPV entry mechanisms.
• The dense glycan shield differs from related viruses like hRSV, impacting vaccine design.
• These findings are critical for the rational development of novel hMPV vaccine candidates.