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Title: Structural basis for recognition of the central conserved region of RSV G by neutralizing human antibodies

Abstract

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants and the elderly, and yet there remains no effective treatment or vaccine. The surface of the virion is decorated with the fusion glycoprotein (RSV F) and the attachment glycoprotein (RSV G), which binds to CX3CR1 on human airway epithelial cells to mediate viral attachment and subsequent infection. RSV G is a major target of the humoral immune response, and antibodies that target the central conserved region of G have been shown to neutralize both subtypes of RSV and to protect against severe RSV disease in animal models. However, the molecular underpinnings for antibody recognition of this region have remained unknown. Therefore, we isolated two human antibodies directed against the central conserved region of RSV G and demonstrated that they neutralize RSV infection of human bronchial epithelial cell cultures in the absence of complement. Moreover, the antibodies protected cotton rats from severe RSV disease. Both antibodies bound with high affinity to a secreted form of RSV G as well as to a peptide corresponding to the unglycosylated central conserved region. High-resolution crystal structures of each antibody in complex with the G peptide revealed two distinctmore » conformational epitopes that require proper folding of the cystine noose located in the C-terminal part of the central conserved region. Comparison of these structures with the structure of fractalkine (CX3CL1) alone or in complex with a viral homolog of CX3CR1 (US28) suggests that RSV G would bind to CX3CR1 in a mode that is distinct from that of fractalkine. Collectively, these results build on recent studies demonstrating the importance of RSV G in antibody-mediated protection from severe RSV disease, and the structural information presented here should guide the development of new vaccines and antibody-based therapies for RSV.« less

Authors:
 [1]; ORCiD logo [2]; ORCiD logo [3];  [2]; ORCiD logo [3];  [2]; ORCiD logo [4];  [5];  [1]; ORCiD logo [6];  [4]; ORCiD logo [7]; ORCiD logo [2]; ORCiD logo [1];  [8]
  1. Univ. of Texas, Austin, TX (United States); Geisel School of Medicine at Dartmouth, Hanover, NH (United States)
  2. Janssen Vaccines & Prevention, Leiden (The Netherlands)
  3. Janssen Pharmaceutical Companies of Johnson and Johnson, San Diego, CA (United States)
  4. Janssen Pharmaceutica NV, Beerse (Belgium)
  5. Janssen R&D US, San Diego, CA (United States)
  6. Janssen Pharmaceutical Companies of Johnson and Johnson, London (United Kingdom)
  7. Janssen Vaccines & Prevention B.V., Leiden (The Netherlands)
  8. National Inst. of Health (NIH), Bethesda, MD (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division; NIH, Office of Research Infrastructure Programs
OSTI Identifier:
1484790
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
PLoS Pathogens
Additional Journal Information:
Journal Volume: 14; Journal Issue: 3; Journal ID: ISSN 1553-7374
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; antibodies; crystal structure; enzyme-linked immunoassays; epithelial cells; respiratory infections; prophylaxis; viral attachment; virus glycoproteins

Citation Formats

Jones, Harrison G., Ritschel, Tina, Pascual, Gabriel, Brakenhoff, Just P. J., Keogh, Elissa, Furmanova-Hollenstein, Polina, Lanckacker, Ellen, Wadia, Jehangir S., Gilman, Morgan S. A., Williamson, R. Anthony, Roymans, Dirk, van ‘t Wout, Angélique B., Langedijk, Johannes P., McLellan, Jason S., and Pierson, Ted C. Structural basis for recognition of the central conserved region of RSV G by neutralizing human antibodies. United States: N. p., 2018. Web. doi:10.1371/journal.ppat.1006935.
Jones, Harrison G., Ritschel, Tina, Pascual, Gabriel, Brakenhoff, Just P. J., Keogh, Elissa, Furmanova-Hollenstein, Polina, Lanckacker, Ellen, Wadia, Jehangir S., Gilman, Morgan S. A., Williamson, R. Anthony, Roymans, Dirk, van ‘t Wout, Angélique B., Langedijk, Johannes P., McLellan, Jason S., & Pierson, Ted C. Structural basis for recognition of the central conserved region of RSV G by neutralizing human antibodies. United States. doi:10.1371/journal.ppat.1006935.
Jones, Harrison G., Ritschel, Tina, Pascual, Gabriel, Brakenhoff, Just P. J., Keogh, Elissa, Furmanova-Hollenstein, Polina, Lanckacker, Ellen, Wadia, Jehangir S., Gilman, Morgan S. A., Williamson, R. Anthony, Roymans, Dirk, van ‘t Wout, Angélique B., Langedijk, Johannes P., McLellan, Jason S., and Pierson, Ted C. Tue . "Structural basis for recognition of the central conserved region of RSV G by neutralizing human antibodies". United States. doi:10.1371/journal.ppat.1006935. https://www.osti.gov/servlets/purl/1484790.
@article{osti_1484790,
title = {Structural basis for recognition of the central conserved region of RSV G by neutralizing human antibodies},
author = {Jones, Harrison G. and Ritschel, Tina and Pascual, Gabriel and Brakenhoff, Just P. J. and Keogh, Elissa and Furmanova-Hollenstein, Polina and Lanckacker, Ellen and Wadia, Jehangir S. and Gilman, Morgan S. A. and Williamson, R. Anthony and Roymans, Dirk and van ‘t Wout, Angélique B. and Langedijk, Johannes P. and McLellan, Jason S. and Pierson, Ted C.},
abstractNote = {Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants and the elderly, and yet there remains no effective treatment or vaccine. The surface of the virion is decorated with the fusion glycoprotein (RSV F) and the attachment glycoprotein (RSV G), which binds to CX3CR1 on human airway epithelial cells to mediate viral attachment and subsequent infection. RSV G is a major target of the humoral immune response, and antibodies that target the central conserved region of G have been shown to neutralize both subtypes of RSV and to protect against severe RSV disease in animal models. However, the molecular underpinnings for antibody recognition of this region have remained unknown. Therefore, we isolated two human antibodies directed against the central conserved region of RSV G and demonstrated that they neutralize RSV infection of human bronchial epithelial cell cultures in the absence of complement. Moreover, the antibodies protected cotton rats from severe RSV disease. Both antibodies bound with high affinity to a secreted form of RSV G as well as to a peptide corresponding to the unglycosylated central conserved region. High-resolution crystal structures of each antibody in complex with the G peptide revealed two distinct conformational epitopes that require proper folding of the cystine noose located in the C-terminal part of the central conserved region. Comparison of these structures with the structure of fractalkine (CX3CL1) alone or in complex with a viral homolog of CX3CR1 (US28) suggests that RSV G would bind to CX3CR1 in a mode that is distinct from that of fractalkine. Collectively, these results build on recent studies demonstrating the importance of RSV G in antibody-mediated protection from severe RSV disease, and the structural information presented here should guide the development of new vaccines and antibody-based therapies for RSV.},
doi = {10.1371/journal.ppat.1006935},
journal = {PLoS Pathogens},
issn = {1553-7374},
number = 3,
volume = 14,
place = {United States},
year = {2018},
month = {3}
}

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    Role of Type I Interferon (IFN) in the Respiratory Syncytial Virus (RSV) Immune Response and Disease Severity
    journal, March 2019