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

Author

Listed:
  • Michael B. Battles

    (Geisel School of Medicine at Dartmouth)

  • Vicente Más

    (Unidad de Biología Viral, Centro Nacional de Microbiología and CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III)

  • Eduardo Olmedillas

    (Unidad de Biología Viral, Centro Nacional de Microbiología and CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III)

  • Olga Cano

    (Unidad de Biología Viral, Centro Nacional de Microbiología and CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III)

  • Mónica Vázquez

    (Unidad de Biología Viral, Centro Nacional de Microbiología and CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III)

  • Laura Rodríguez

    (Unidad de Biología Viral, Centro Nacional de Microbiología and CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III
    University of Rochester Medical Center)

  • José A. Melero

    (Unidad de Biología Viral, Centro Nacional de Microbiología and CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III)

  • Jason S. McLellan

    (Geisel School of Medicine at Dartmouth)

Abstract

Human metapneumovirus (hMPV) is a frequent cause of bronchiolitis in young children. Its F glycoprotein mediates virus–cell membrane fusion and is the primary target of neutralizing antibodies. The inability to produce recombinant hMPV F glycoprotein in the metastable pre-fusion conformation has hindered structural and immunological studies. Here, we engineer a pre-fusion-stabilized hMPV F ectodomain and determine its crystal structure to 2.6 Å resolution. This structure reveals molecular determinants of strain-dependent acid-induced fusion, as well as insights into refolding from pre- to post-fusion conformations. A dense glycan shield at the apex of pre-fusion hMPV F suggests that antibodies against this site may not be elicited by host immune responses, which is confirmed by depletion studies of human immunoglobulins and by mouse immunizations. This is a major difference with pre-fusion F from human respiratory syncytial virus (hRSV), and collectively our results should facilitate development of effective hMPV vaccine candidates.

Suggested Citation

  • Michael B. Battles & Vicente Más & Eduardo Olmedillas & Olga Cano & Mónica Vázquez & Laura Rodríguez & José A. Melero & Jason S. McLellan, 2017. "Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01708-9
    DOI: 10.1038/s41467-017-01708-9
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    Citations

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    Cited by:

    1. Karen J. Gonzalez & Jiachen Huang & Miria F. Criado & Avik Banerjee & Stephen M. Tompkins & Jarrod J. Mousa & Eva-Maria Strauch, 2024. "A general computational design strategy for stabilizing viral class I fusion proteins," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Ching-Lin Hsieh & Scott A. Rush & Concepcion Palomo & Chia-Wei Chou & Whitney Pickens & Vicente Más & Jason S. McLellan, 2022. "Structure-based design of prefusion-stabilized human metapneumovirus fusion proteins," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Mark J. G. Bakkers & Tina Ritschel & Machteld Tiemessen & Jacobus Dijkman & Angelo A. Zuffianò & Xiaodi Yu & Daan Overveld & Lam Le & Richard Voorzaat & Marlies M. Haaren & Martijn Man & Sem Tamara & , 2024. "Efficacious human metapneumovirus vaccine based on AI-guided engineering of a closed prefusion trimer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Johannes P. M. Langedijk & Freek Cox & Nicole V. Johnson & Daan Overveld & Lam Le & Ward Hoogen & Richard Voorzaat & Roland Zahn & Leslie Fits & Jarek Juraszek & Jason S. McLellan & Mark J. G. Bakkers, 2024. "Universal paramyxovirus vaccine design by stabilizing regions involved in structural transformation of the fusion protein," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Tara C. Marcink & Gillian Zipursky & Elizabeth B. Sobolik & Kate Golub & Emily Herman & Kyle Stearns & Alexander L. Greninger & Matteo Porotto & Anne Moscona, 2024. "How a paramyxovirus fusion/entry complex adapts to escape a neutralizing antibody," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. Xiao Xiao & Arthur Fridman & Lu Zhang & Pavlo Pristatsky & Eberhard Durr & Michael Minnier & Aimin Tang & Kara S. Cox & Zhiyun Wen & Renee Moore & Dongrui Tian & Jennifer D. Galli & Scott Cosmi & Mich, 2022. "Profiling of hMPV F-specific antibodies isolated from human memory B cells," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Madelyn Cabán & Justas V. Rodarte & Madeleine Bibby & Matthew D. Gray & Justin J. Taylor & Marie Pancera & Jim Boonyaratanakornkit, 2023. "Cross-protective antibodies against common endemic respiratory viruses," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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