Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation
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 vacci...
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Published in: | PLoS pathogens Vol. 12; no. 9; p. e1005859 |
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Main Authors: | , , , , , , , , |
Format: | Journal Article |
Language: | English |
Published: |
United States
Public Library of Science
01-09-2016
Public Library of Science (PLoS) |
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Online Access: | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AC02-06CH11357; SAF2015-67033-RSAF2012-31217; BFU 2013-43149-R; P20GM113132 National Inst. of Health USDOE Office of Science (SC), Biological and Environmental Research (BER) Conceived and designed the experiments: VM DL JAM JSM. Performed the experiments: VM LR EO OC CP MCT DL JSM. Analyzed the data: VM LR EO OC CP MCT DL JAM JSM. Wrote the paper: VM DL JAM JSM. Current address: University of Rochester Medical Center, Rochester, New York, United States of America The authors have declared that no competing interests exist. |
ISSN: | 1553-7374 1553-7366 1553-7374 |
DOI: | 10.1371/journal.ppat.1005859 |