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

Jones HG, Ritschel T, Pascual G, Brakenhoff JPJ, Keogh E, Furmanova-Hollenstein P, Lanckacker E, Wadia JS, Gilman MSA, Williamson RA, Roymans D, van 't Wout AB, Langedijk JP, McLellan JS
PLoS Pathog 14 e1006935 (2018)
Cited: 36 times
EuropePMC logo PMID: 29509814

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 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.

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  2. Molecular mimicry of host short linear motif-mediated interactions utilised by viruses for entry. Goswami S, Samanta D, Duraivelan K. Mol Biol Rep 50 4665-4673 (2023)

Articles - 6blh mentioned but not cited (3)

  1. Structural basis for recognition of the central conserved region of RSV G by neutralizing human antibodies. Jones HG, Ritschel T, Pascual G, Brakenhoff JPJ, Keogh E, Furmanova-Hollenstein P, Lanckacker E, Wadia JS, Gilman MSA, Williamson RA, Roymans D, van 't Wout AB, Langedijk JP, McLellan JS. PLoS Pathog 14 e1006935 (2018)
  2. Structure-Based Design and Antigenic Validation of Respiratory Syncytial Virus G Immunogens. Nuñez Castrejon AM, O'Rourke SM, Kauvar LM, DuBois RM. J Virol 96 e0220121 (2022)
  3. Respiratory syncytial virus reduces STAT3 phosphorylation in human memory CD8 T cells stimulated with IL-21. Antunes KH, Becker A, Franceschina C, de Freitas DDN, Lape I, da Cunha MD, Leitão L, Rigo MM, Pinto LA, Stein RT, de Souza APD. Sci Rep 9 17766 (2019)


Reviews citing this publication (14)

  1. Respiratory syncytial virus entry and how to block it. Battles MB, McLellan JS. Nat Rev Microbiol 17 233-245 (2019)
  2. Role of Type I Interferon (IFN) in the Respiratory Syncytial Virus (RSV) Immune Response and Disease Severity. Hijano DR, Vu LD, Kauvar LM, Tripp RA, Polack FP, Cormier SA. Front Immunol 10 566 (2019)
  3. Immunopathology of RSV: An Updated Review. Bergeron HC, Tripp RA. Viruses 13 2478 (2021)
  4. A Contemporary View of Respiratory Syncytial Virus (RSV) Biology and Strain-Specific Differences. Pandya MC, Callahan SM, Savchenko KG, Stobart CC. Pathogens 8 E67 (2019)
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  6. Antibody Epitopes of Pneumovirus Fusion Proteins. Huang J, Diaz D, Mousa JJ. Front Immunol 10 2778 (2019)
  7. Functional Features of the Respiratory Syncytial Virus G Protein. Anderson LJ, Jadhao SJ, Paden CR, Tong S. Viruses 13 1214 (2021)
  8. Innate Immune Components that Regulate the Pathogenesis and Resolution of hRSV and hMPV Infections. Andrade CA, Pacheco GA, Gálvez NMS, Soto JA, Bueno SM, Kalergis AM. Viruses 12 E637 (2020)
  9. Exploring the potential of foodborne transmission of respiratory viruses. O'Brien B, Goodridge L, Ronholm J, Nasheri N. Food Microbiol 95 103709 (2021)
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  12. Computational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals. Bozhanova NG, Flyak AI, Brown BP, Ruiz SE, Salas J, Rho S, Bombardi RG, Myers L, Soto C, Bailey JR, Crowe JE, Bjorkman PJ, Meiler J. Nat Commun 13 3178 (2022)
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Articles citing this publication (17)

  1. Multiepitope-Based Subunit Vaccine Design and Evaluation against Respiratory Syncytial Virus Using Reverse Vaccinology Approach. Tahir Ul Qamar M, Shokat Z, Muneer I, Ashfaq UA, Javed H, Anwar F, Bari A, Zahid B, Saari N. Vaccines (Basel) 8 E288 (2020)
  2. Protective antigenic sites in respiratory syncytial virus G attachment protein outside the central conserved and cysteine noose domains. Lee J, Klenow L, Coyle EM, Golding H, Khurana S. PLoS Pathog 14 e1007262 (2018)
  3. Effects of Alterations to the CX3C Motif and Secreted Form of Human Respiratory Syncytial Virus (RSV) G Protein on Immune Responses to a Parainfluenza Virus Vector Expressing the RSV G Protein. Liang B, Kabatova B, Kabat J, Dorward DW, Liu X, Surman S, Liu X, Moseman AP, Buchholz UJ, Collins PL, Munir S. J Virol 93 e02043-18 (2019)
  4. CX3CR1 Engagement by Respiratory Syncytial Virus Leads to Induction of Nucleolin and Dysregulation of Cilia-related Genes. Anderson CS, Chirkova T, Slaunwhite CG, Qiu X, Walsh EE, Anderson LJ, Mariani TJ. J Virol 95 JVI.00095-21 (2021)
  5. Conformational Flexibility in Respiratory Syncytial Virus G Neutralizing Epitopes. Fedechkin SO, George NL, Nuñez Castrejon AM, Dillen JR, Kauvar LM, DuBois RM. J Virol 94 e01879-19 (2020)
  6. Respiratory Syncytial Virus (RSV) G Protein Vaccines With Central Conserved Domain Mutations Induce CX3C-CX3CR1 Blocking Antibodies. Bergeron HC, Murray J, Nuñez Castrejon AM, DuBois RM, Tripp RA. Viruses 13 352 (2021)
  7. Biophysical and flavonoid-binding studies of the G protein ectodomain of group A human respiratory syncytial virus. Machado VB, Maróstica de Sá J, Miranda Prado AK, Alves de Toledo K, Regasini LO, Pereira de Souza F, Caruso ÍP, Fossey MA. Heliyon 5 e01394 (2019)
  8. Combinatorial F-G Immunogens as Nipah and Respiratory Syncytial Virus Vaccine Candidates. Isaacs A, Cheung STM, Thakur N, Jaberolansar N, Young A, Modhiran N, Bailey D, Graham SP, Young PR, Chappell KJ, Watterson D. Viruses 13 1942 (2021)
  9. Evolution of respiratory syncytial virus genotype BA in Kilifi, Kenya, 15 years on. Kamau E, Otieno JR, Lewa CS, Mwema A, Murunga N, Nokes DJ, Agoti CN. Sci Rep 10 21176 (2020)
  10. Features of the Human Antibody Response against the Respiratory Syncytial Virus Surface Glycoprotein G. Borochova K, Niespodziana K, Stenberg Hammar K, van Hage M, Hedlin G, Söderhäll C, Focke-Tejkl M, Valenta R. Vaccines (Basel) 8 E337 (2020)
  11. Development of Luciferase Immunoprecipitation Systems (LIPS) Assay to Detect IgG Antibodies against Human Respiratory Syncytial Virus G-Glycoprotein. Crim RL, Kumari S, Jayanti P, Audet S, Kulkarni A, Beeler J. Vaccines (Basel) 7 E16 (2019)
  12. Evolutionary dynamics of group A and B respiratory syncytial virus in China, 2009-2018. Ma Y, Jiang H, Wan Z, Li S, Li Y, Wang W, Jin X, Li Y, Zhang C. Arch Virol 166 2407-2418 (2021)
  13. Immunogenicity and protective efficacy of RSV G central conserved domain vaccine with a prefusion nanoparticle. Rainho-Tomko JN, Pavot V, Kishko M, Swanson K, Edwards D, Yoon H, Lanza L, Alamares-Sapuay J, Osei-Bonsu R, Mundle ST, Murison DA, Gallichan S, Delagrave S, Wei CJ, Zhang L, Nabel GJ. NPJ Vaccines 7 74 (2022)
  14. Ephedrae Herba and Cinnamomi Cortex interactions with G glycoprotein inhibit respiratory syncytial virus infectivity. Fujikane A, Sakamoto A, Fujikane R, Nishi A, Ishino Y, Hiromatsu K, Nabeshima S. Commun Biol 5 94 (2022)
  15. Structural Characterization and Binding Studies of the Ectodomain G Protein of Respiratory Syncytial Virus Reveal the Crucial Role of pH with Possible Implications in Host-Pathogen Interactions. Hamza A, Shafat Z, Parray ZA, Hisamuddin M, Khan WH, Ahmed A, Almajhdi FN, Farrag MA, Mohammed AA, Islam A, Parveen S, Parveen S. ACS Omega 6 10403-10414 (2021)
  16. Analysis of circulating respiratory syncytial virus A strains in Shanghai, China identified a new and increasingly prevalent lineage within the dominant ON1 genotype. Zhao X, Wang C, Jiang H, Zhang H, Fang F, Chen M, Yuan Z, Teng Z, Liu J, Zhang X. Front Microbiol 13 966235 (2022)
  17. Immunogenicity and protective efficacy of an RSV G S177Q central conserved domain nanoparticle vaccine. Bergeron HC, Murray J, Juarez MG, Nangle SJ, DuBois RM, Tripp RA. Front Immunol 14 1215323 (2023)


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