Convergent structural features of respiratory syncytial virus neutralizing antibodies and plasticity of the site V epitope on prefusion F

Autor: Nurjahan Mehzabeen, Matthew J. Bottomley, Sai Tian, Wayne Harshbarger, Diana Chinchilla-Olszar, Sumana Chandramouli, Zihao Wang, Marco Biancucci, Deep S. Bhattacharya, Kristian Friedrich, Ying Huang, Newton Muchugu Wahome, Desheng Jiang, Corey P. Mallett, Enrico Malito, Ratnesh Pandey, Ankita Balsaraf, Kunal Tungare
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Physiology
Antibodies
Viral
Crystallography
X-Ray
01 natural sciences
Biochemistry
Epitope
Epitopes
Aromatic Amino Acids
Immunogenicity
Vaccine
Immune Physiology
Medicine and Health Sciences
Electrochemistry
Public and Occupational Health
Salt Bridges
Respiratory system
Biology (General)
Amino Acids
Neutralizing antibody
Immune Response
chemistry.chemical_classification
0303 health sciences
Immune System Proteins
Crystallography
010304 chemical physics
Organic Compounds
Immunogenicity
Physics
Condensed Matter Physics
Vaccination and Immunization
Respiratory Syncytial Viruses
Chemistry
Physical Sciences
Crystal Structure
Antibody
Research Article
QH301-705.5
Immunology
Respiratory Syncytial Virus Infections
Biology
Microbiology
Virus
Antibodies
03 medical and health sciences
Virology
Hydroxyl Amino Acids
0103 physical sciences
Vaccine Development
Genetics
Respiratory Syncytial Virus Vaccines
Solid State Physics
Point Mutation
Animals
Humans
Antigens
Molecular Biology
030304 developmental biology
Organic Chemistry
Chemical Compounds
Biology and Life Sciences
Proteins
RC581-607
Antibodies
Neutralizing
Models
Structural
Immunization
chemistry
Mutation
biology.protein
Tyrosine
Parasitology
Cattle
Preventive Medicine
Immunologic diseases. Allergy
Glycoprotein
Viral Fusion Proteins
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 16, Iss 11, p e1008943 (2020)
ISSN: 1553-7374
1553-7366
Popis: Respiratory syncytial virus (RSV) is a global public health burden for which no licensed vaccine exists. To aid vaccine development via increased understanding of the protective antibody response to RSV prefusion glycoprotein F (PreF), we performed structural and functional studies using the human neutralizing antibody (nAb) RSB1. The crystal structure of PreF complexed with RSB1 reveals a conformational, pre-fusion specific site V epitope with a unique cross-protomer binding mechanism. We identify shared structural features between nAbs RSB1 and CR9501, elucidating for the first time how diverse germlines obtained from different subjects can develop convergent molecular mechanisms for recognition of the same PreF site of vulnerability. Importantly, RSB1-like nAbs were induced upon immunization with PreF in naturally-primed cattle. Together, this work reveals new details underlying the immunogenicity of site V and further supports PreF-based vaccine development efforts.
Author summary Respiratory syncytial virus (RSV) is a persistent, contagious seasonal pathogen and a serious public health threat. While infants are the most at-risk population, with infections potentially leading to bronchiolitis, adults, especially the elderly, are also burdened by RSV-induced respiratory infections. The only treatment currently available for RSV is passive immunization for high-risk infants. Thus, there is a critical need to develop a vaccine for the vast majority of the vulnerable population for which there is no preventative treatment. The RSV fusion protein in its prefusion form (PreF) is the target of the majority of naturally-induced neutralizing antibodies, and several clinical trials are currently evaluating PreF as a promising vaccine candidate. In this study, we solved the X-ray structure of PreF bound to the Fab fragment of a human neutralizing antibody. The structure reveals plasticity of the epitope, as well as a unique molecular signature for antibodies elicited towards this region of PreF. We also find that similar antibodies are induced upon immunization of naturally-primed cattle with a PreF vaccine antigen, suggesting that this epitope is highly immunogenic. These results will help us better understand the human immune response to RSV infection and vaccination, and guide future vaccine-design efforts.
Databáze: OpenAIRE
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