Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation

Más, Vicente; Rodriguez, Laura; Olmedillas, Eduardo; Cano, Olga; Palomo, Concepción; Terrón, María C.; Luque, Daniel; Melero, José A.; McLellan, Jason S.; Plemper, Richard K.

doi:10.1371/journal.ppat.1005859

Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation

Journal Article · Fri Sep 09 00:00:00 EDT 2016 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1005859· OSTI ID:1324810

Más, Vicente ^[1]; Rodriguez, Laura ^[2]; Olmedillas, Eduardo ^[1]; Cano, Olga ^[1]; Palomo, Concepción ^[1]; Terrón, María C. ^[1]; Luque, Daniel ^[1]; Melero, José A. ^[1]; McLellan, Jason S. ^[3]; Plemper, Richard K. ^[4]

Inst. de Salud Carlos III, Madrid (Spain)
Univ. of Rochester Medical Center, NY (United States); Inst. de Salud Carlos III, Madrid (Spain)
Geisel School of Medicine at Dartmouth, Hanover, NH (United States)
Georgia State Univ., Atlanta, GA (United States)

Human metapneumovirus (hMPV) is a paramyxovirus that is a common cause of bronchiolitis and pneumonia in children less than five years of age. The hMPV fusion (F) glycoprotein is the primary target of neutralizing antibodies and is thus a critical vaccine antigen. To facilitate structure-based vaccine design, we stabilized the ectodomain of the hMPV F protein in the postfusion conformation and determined its structure to a resolution of 3.3 Å by X-ray crystallography. The structure resembles an elongated cone and is very similar to the postfusion F protein from the related human respiratory syncytial virus (hRSV). In contrast, significant differences were apparent with the postfusion F proteins from other paramyxoviruses, such as human parainfluenza type 3 (hPIV3) and Newcastle disease virus (NDV). The high similarity of hMPV and hRSV postfusion F in two antigenic sites targeted by neutralizing antibodies prompted us to test for antibody cross-reactivity. The widely used monoclonal antibody 101F, which binds to antigenic site IV of hRSV F, was found to cross-react with hMPV postfusion F and neutralize both hRSV and hMPV. Despite the cross-reactivity of 101F and the reported cross-reactivity of two other antibodies, 54G10 and MPE8, we found no detectable cross-reactivity in the polyclonal antibody responses raised in mice against the postfusion forms of either hMPV or hRSV F. The postfusion-stabilized hMPV F protein did, however, elicit high titers of hMPV-neutralizing activity, suggesting that it could serve as an effective subunit vaccine. Structural insights from these studies should be useful for designing novel immunogens able to induce wider cross-reactive antibody responses.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1324810

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 9 Vol. 12; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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An S101P Substitution in the Putative Cleavage Motif of the Human Metapneumovirus Fusion Protein Is a Major Determinant for Trypsin-Independent Growth in Vero Cells and Does Not Alter Tissue Tropism in Hamsters Schickli, Jeanne H.; Kaur, Jasmine; Ulbrandt, Nancy Journal of Virology, Vol. 79, Issue 16 https://doi.org/10.1128/JVI.79.16.10678-10689.2005	journal	August 2005
Respiratory Syncytial Virus Fusion Glycoprotein Expressed in Insect Cells Form Protein Nanoparticles That Induce Protective Immunity in Cotton Rats Smith, Gale; Raghunandan, Rama; Wu, Yingyun PLoS ONE, Vol. 7, Issue 11 https://doi.org/10.1371/journal.pone.0050852	journal	November 2012
Antigenic and Genetic Variability of Human Metapneumoviruses van den Hoogen, Bernadette G.; Herfst, Sander; Sprong, Leo Emerging Infectious Diseases, Vol. 10, Issue 4 https://doi.org/10.3201/eid1004.030393	journal	April 2004

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Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein Battles, Michael B.; Más, Vicente; Olmedillas, Eduardo Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-01708-9	journal	November 2017
Characterization of potent RSV neutralizing antibodies isolated from human memory B cells and identification of diverse RSV/hMPV cross-neutralizing epitopes Xiao, Xiao; Tang, Aimin; Cox, Kara S. mAbs, Vol. 11, Issue 8 https://doi.org/10.1080/19420862.2019.1654304	journal	August 2019
Inhibiting Human Parainfluenza Virus Infection by Preactivating the Cell Entry Mechanism Bottom-Tanzer, S. F.; Rybkina, K.; Bell, J. N. mBio, Vol. 10, Issue 1 https://doi.org/10.1128/mbio.02900-18	journal	February 2019
Human antibody recognition of antigenic site IV on Pneumovirus fusion proteins Mousa, Jarrod J.; Binshtein, Elad; Human, Stacey PLOS Pathogens, Vol. 14, Issue 2 https://doi.org/10.1371/journal.ppat.1006837	journal	February 2018
Antibody Epitopes of Pneumovirus Fusion Proteins Huang, Jiachen; Diaz, Darren; Mousa, Jarrod J. Frontiers in Immunology, Vol. 10 https://doi.org/10.3389/fimmu.2019.02778	journal	November 2019
The Complexity of Antibody Responses Elicited against the Respiratory Syncytial Virus Glycoproteins in Hospitalized Children Younger than 2 Years Trento, Alfonsina; Rodríguez-Fernández, Rosa; González-Sánchez, María I. Frontiers in Microbiology, Vol. 8 https://doi.org/10.3389/fmicb.2017.02301	journal	November 2017
A Potent Neutralizing Site III-Specific Human Antibody Neutralizes Human Metapneumovirus In Vivo Bar-Peled, Yael; Diaz, Darren; Pena-Briseno, Alma Journal of Virology, Vol. 93, Issue 19 https://doi.org/10.1128/jvi.00342-19	journal	July 2019

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