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

Michael B. Battles, Vicente Más, Eduardo Olmedillas, Olga Cano, Mónica Vázquez, Laura Rodríguez, José A. Melero () and Jason S. McLellan ()
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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
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

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01708-9

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