Antibody recognition of the Pneumovirus fusion protein trimer interface

Human metapneumovirus (hMPV) is a leading cause of viral respiratory infection in children, and can cause severe lower respiratory tract infection in infants, the elderly, and immunocompromised patients. However, there remain no licensed vaccines or specific treatments for hMPV infection. Although t...

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Published inPLoS pathogens Vol. 16; no. 10; p. e1008942
Main Authors Huang, Jiachen, Diaz, Darren, Mousa, Jarrod J.
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 09.10.2020
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Abstract Human metapneumovirus (hMPV) is a leading cause of viral respiratory infection in children, and can cause severe lower respiratory tract infection in infants, the elderly, and immunocompromised patients. However, there remain no licensed vaccines or specific treatments for hMPV infection. Although the hMPV fusion (F) protein is the sole target of neutralizing antibodies, the immunological properties of hMPV F remain poorly understood. To further define the humoral immune response to the hMPV F protein, we isolated two new human monoclonal antibodies (mAbs), MPV458 and MPV465. Both mAbs are neutralizing in vitro and were determined to target a unique antigenic site using competitive biolayer interferometry. We determined both MPV458 and MPV465 have higher affinity for monomeric hMPV F than trimeric hMPV F. MPV458 was co-crystallized with hMPV F, and the mAb primarily interacts with an alpha helix on the F2 region of the hMPV F protein. Surprisingly, the major epitope for MPV458 lies within the trimeric interface of the hMPV F protein, suggesting significant breathing of the hMPV F protein must occur for host immune recognition of the novel epitope. In addition, significant glycan interactions were observed with a somatically mutated light chain framework residue. The data presented identifies a novel epitope on the hMPV F protein for epitope-based vaccine design, and illustrates a new mechanism for human antibody neutralization of viral glycoproteins.
AbstractList Human metapneumovirus (hMPV) is a leading cause of viral respiratory infection in children, and can cause severe lower respiratory tract infection in infants, the elderly, and immunocompromised patients. However, there remain no licensed vaccines or specific treatments for hMPV infection. Although the hMPV fusion (F) protein is the sole target of neutralizing antibodies, the immunological properties of hMPV F remain poorly understood. To further define the humoral immune response to the hMPV F protein, we isolated two new human monoclonal antibodies (mAbs), MPV458 and MPV465. Both mAbs are neutralizing in vitro and were determined to target a unique antigenic site using competitive biolayer interferometry. We determined both MPV458 and MPV465 have higher affinity for monomeric hMPV F than trimeric hMPV F. MPV458 was co-crystallized with hMPV F, and the mAb primarily interacts with an alpha helix on the F2 region of the hMPV F protein. Surprisingly, the major epitope for MPV458 lies within the trimeric interface of the hMPV F protein, suggesting significant breathing of the hMPV F protein must occur for host immune recognition of the novel epitope. In addition, significant glycan interactions were observed with a somatically mutated light chain framework residue. The data presented identifies a novel epitope on the hMPV F protein for epitope-based vaccine design, and illustrates a new mechanism for human antibody neutralization of viral glycoproteins.
Human metapneumovirus (hMPV) is a leading cause of viral respiratory infection in children, and can cause severe lower respiratory tract infection in infants, the elderly, and immunocompromised patients. However, there remain no licensed vaccines or specific treatments for hMPV infection. Although the hMPV fusion (F) protein is the sole target of neutralizing antibodies, the immunological properties of hMPV F remain poorly understood. To further define the humoral immune response to the hMPV F protein, we isolated two new human monoclonal antibodies (mAbs), MPV458 and MPV465. Both mAbs are neutralizing in vitro and were determined to target a unique antigenic site using competitive biolayer interferometry. We determined both MPV458 and MPV465 have higher affinity for monomeric hMPV F than trimeric hMPV F. MPV458 was co-crystallized with hMPV F, and the mAb primarily interacts with an alpha helix on the F2 region of the hMPV F protein. Surprisingly, the major epitope for MPV458 lies within the trimeric interface of the hMPV F protein, suggesting significant breathing of the hMPV F protein must occur for host immune recognition of the novel epitope. In addition, significant glycan interactions were observed with a somatically mutated light chain framework residue. The data presented identifies a novel epitope on the hMPV F protein for epitope-based vaccine design, and illustrates a new mechanism for human antibody neutralization of viral glycoproteins.Human metapneumovirus (hMPV) is a leading cause of viral respiratory infection in children, and can cause severe lower respiratory tract infection in infants, the elderly, and immunocompromised patients. However, there remain no licensed vaccines or specific treatments for hMPV infection. Although the hMPV fusion (F) protein is the sole target of neutralizing antibodies, the immunological properties of hMPV F remain poorly understood. To further define the humoral immune response to the hMPV F protein, we isolated two new human monoclonal antibodies (mAbs), MPV458 and MPV465. Both mAbs are neutralizing in vitro and were determined to target a unique antigenic site using competitive biolayer interferometry. We determined both MPV458 and MPV465 have higher affinity for monomeric hMPV F than trimeric hMPV F. MPV458 was co-crystallized with hMPV F, and the mAb primarily interacts with an alpha helix on the F2 region of the hMPV F protein. Surprisingly, the major epitope for MPV458 lies within the trimeric interface of the hMPV F protein, suggesting significant breathing of the hMPV F protein must occur for host immune recognition of the novel epitope. In addition, significant glycan interactions were observed with a somatically mutated light chain framework residue. The data presented identifies a novel epitope on the hMPV F protein for epitope-based vaccine design, and illustrates a new mechanism for human antibody neutralization of viral glycoproteins.
Human metapneumovirus (hMPV) is a leading cause of viral respiratory infection in children, and can cause severe lower respiratory tract infection in infants, the elderly, and immunocompromised patients. However, there remain no licensed vaccines or specific treatments for hMPV infection. Although the hMPV fusion (F) protein is the sole target of neutralizing antibodies, the immunological properties of hMPV F remain poorly understood. To further define the humoral immune response to the hMPV F protein, we isolated two new human monoclonal antibodies (mAbs), MPV458 and MPV465. Both mAbs are neutralizing in vitro and were determined to target a unique antigenic site using competitive biolayer interferometry. We determined both MPV458 and MPV465 have higher affinity for monomeric hMPV F than trimeric hMPV F. MPV458 was co-crystallized with hMPV F, and the mAb primarily interacts with an alpha helix on the F2 region of the hMPV F protein. Surprisingly, the major epitope for MPV458 lies within the trimeric interface of the hMPV F protein, suggesting significant breathing of the hMPV F protein must occur for host immune recognition of the novel epitope. In addition, significant glycan interactions were observed with a somatically mutated light chain framework residue. The data presented identifies a novel epitope on the hMPV F protein for epitope-based vaccine design, and illustrates a new mechanism for human antibody neutralization of viral glycoproteins. Human metapneumovirus (hMPV) is a common cause of lower respiratory tract infection in children, the elderly, and the immunocompromised. There is currently no approved vaccine or therapeutic to prevent or treat hMPV infection. The hMPV fusion (F) protein is the sole target of antibodies that neutralize hMPV. Here we describe new human mAbs that bind a unique epitope on the hMPV F protein. The mAbs were mapped to a new antigenic site on the hMPV F protein located within the trimeric interface of the hMPV F protein based on competitive biolayer interferometry and X-ray crystallographic experiments. This is the first example of a human mAb that binds inside the trimeric interface of a viral glycoprotein and neutralizes the virus. The results suggest such antibodies may exist for other viral fusion proteins, and identify a new epitope on the hMPV F protein for epitope-based vaccine design.
Audience Academic
Author Huang, Jiachen
Mousa, Jarrod J.
Diaz, Darren
AuthorAffiliation 2 Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA, United States of America
1 Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, United States of America
University of Texas Medical Branch / Galveston National Laboratory, UNITED STATES
AuthorAffiliation_xml – name: University of Texas Medical Branch / Galveston National Laboratory, UNITED STATES
– name: 2 Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA, United States of America
– name: 1 Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, United States of America
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  surname: Huang
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  surname: Mousa
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  ident: ppat.1008942.ref024
  article-title: Co-infection with SARS-CoV-2 and Human Metapneumovirus
  publication-title: R I Med J (2013)
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Snippet Human metapneumovirus (hMPV) is a leading cause of viral respiratory infection in children, and can cause severe lower respiratory tract infection in infants,...
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StartPage e1008942
SubjectTerms Antibodies
Antibodies, Monoclonal - immunology
Antibodies, Neutralizing - immunology
Antibodies, Neutralizing - pharmacology
Antibodies, Viral - immunology
Antigens
BASIC BIOLOGICAL SCIENCES
Biology and Life Sciences
Crystallization
Engineering and Technology
Epidemics
Epitopes
Epitopes - immunology
F 2 region
F protein
Fusion protein
Genetic aspects
Glycan
Glycoproteins
Health aspects
Host-virus relationships
Human subjects
Humans
Identification and classification
Immune response
Immune response (humoral)
Immune system
Immunocompromised hosts
Immunology
Infants
Infections
Infectious diseases
Interferometry
Medicine and Health Sciences
Metapneumovirus - immunology
Monoclonal antibodies
Mutation
Neutralization
Neutralizing
Paramyxoviridae Infections - virology
Peptides
Physical Sciences
Pneumovirus - immunology
Proteins
Recognition
Research and Analysis Methods
Respiratory diseases
Respiratory syncytial virus
Respiratory Syncytial Virus, Human - immunology
Respiratory tract
Respiratory tract diseases
RNA viruses
Severe acute respiratory syndrome coronavirus 2
Trimers
Vaccines
Veterinary colleges
Veterinary medicine
Viral Fusion Proteins - immunology
Viral infections
Viral proteins
Viruses
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Title Antibody recognition of the Pneumovirus fusion protein trimer interface
URI https://www.ncbi.nlm.nih.gov/pubmed/33035266
https://www.proquest.com/docview/2460983334
https://www.proquest.com/docview/2449959332
https://www.osti.gov/servlets/purl/1834810
https://pubmed.ncbi.nlm.nih.gov/PMC7598476
https://doaj.org/article/0b622c80f4b045cbb123fd382293faca
http://dx.doi.org/10.1371/journal.ppat.1008942
Volume 16
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