Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Structural basis for antibody cross-neutralization of respiratory syncytial virus and human metapneumovirus

Nature Microbiology volume 2, Article number: 16272 (2017) Cite this article

Subjects

Abstract

Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are two closely related viruses that cause bronchiolitis and pneumonia in infants and the elderly1, with a significant health burden2–6. There are no licensed vaccines or small-molecule antiviral treatments specific to these two viruses at present. A humanized murine monoclonal antibody (palivizumab) is approved to treat high-risk infants for RSV infection7,8, but other treatments, as well as vaccines, for both viruses are still in development. Recent epidemiological modelling suggests that cross-immunity between RSV, HMPV and human parainfluenzaviruses may contribute to their periodic outbreaks9, suggesting that a deeper understanding of host immunity to these viruses may lead to enhanced strategies for their control. Cross-reactive neutralizing antibodies to the RSV and HMPV fusion (F) proteins have been identified10,11. Here, we examine the structural basis for cross-reactive antibody binding to RSV and HMPV F protein by two related, independently isolated antibodies, MPE8 and 25P13. We solved the structure of the MPE8 antibody bound to RSV F protein and identified the 25P13 antibody from an independent blood donor. Our results indicate that both antibodies use germline residues to interact with a conserved surface on F protein that could guide the emergence of cross-reactivity. The induction of similar cross-reactive neutralizing antibodies using structural vaccinology approaches could enhance intrinsic cross-immunity to these paramyxoviruses and approaches to controlling recurring outbreaks.

Most of the MPE8 epitope lies within one subunit of the F trimer, involving residues in DI and DIII, with a smaller contact area in DII of the neighbouring subunit (Fig. 2a). The DIII contacts overlap the helix-turn-helix motif of the palivizumab/motavizumab site A epitope (Fig. 2a,b). The Vh domain lies distal to the F trimer interface, primarily contacting the F surface below and to one edge of site A (Fig. 2a–c). The heavy-chain complementarity-determining region 3 (HCDR3) loop extends underneath the site A motif in DIII to insert its tip into a pocket formed at the intersubunit interface (Fig. 2b,c), with residues Y100 and N100A forming contacts dependent on the prefusion F conformation. HCDR3 residues (100B–100G) interact with the turn residues within site A (Fig. 2b). HCDR2 also forms interactions with the second helix of site A and with residues in DI, while HCDR1 contacts F below site A in DI (Fig. 2c). RSV F mutations that have been shown previously to affect MPE8 binding also map to the structural interface (Supplementary Fig. 5). The mutation of D310A would disrupt interactions with HCDR2 and many of these previously identified mutations line the groove along which HCDR3 extends (L305R, G307R, R49D and T50A).

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overall structure of the RSV F:MPE8 complex.
Figure 2: The MPE8 epitope and paratope.
Figure 3: Structural basis for MPE8 cross-reactivity.
Figure 4: 25P13 is an MPE8-related cross-reactive neutralizing antibody.

References

  1. Collins, P. L. & Karron, R. A. in Fields Virology 6th edn, Vol. 1 (eds Knipe, D. M. & Howley, P. M. ) Ch. 38 (Wolters Kluwer Health Adis (ESP), 2013).

    Google Scholar 

  2. Hall, C. B., Simoes, E. A. & Anderson, L. J. Clinical and epidemiologic features of respiratory syncytial virus. Curr. Top. Microbiol. Immunol. 372, 39–57 (2013).

    PubMed  Google Scholar 

  3. Falsey, A. R., Hennessey, P. A., Formica, M. A., Cox, C. & Walsh, E. E. Respiratory syncytial virus infection in elderly and high-risk adults. N. Engl. J. Med. 352, 1749–1759 (2005).

    Article  CAS  Google Scholar 

  4. Hall, C. B. The burgeoning burden of respiratory syncytial virus among children. Infect. Disord. Drug Targets 12, 92–97 (2012).

    Article  CAS  Google Scholar 

  5. Edwards, K. M. et al. Burden of human metapneumovirus infection in young children. N. Engl. J. Med. 368, 633–643 (2013).

    Article  CAS  Google Scholar 

  6. Williams, J. V. et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N. Engl. J. Med. 350, 443–450 (2004).

    Article  CAS  Google Scholar 

  7. Fenton, C., Scott, L. J. & Plosker, G. L. Palivizumab: a review of its use as prophylaxis for serious respiratory syncytial virus infection. Paediatr. Drugs 6, 177–197 (2004).

    Article  Google Scholar 

  8. The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 102, 531–537 (1998).

    Article  Google Scholar 

  9. Bhattacharyya, S., Gesteland, P. H., Korgenski, K., Bjornstad, O. N. & Adler, F. R. Cross-immunity between strains explains the dynamical pattern of paramyxoviruses. Proc. Natl Acad. Sci. USA 112, 13396–13400 (2015).

    Article  CAS  Google Scholar 

  10. Corti, D. et al. Cross-neutralization of four paramyxoviruses by a human monoclonal antibody. Nature 501, 439–443 (2013).

    Article  CAS  Google Scholar 

  11. Schuster, J. E. et al. A broadly neutralizing human monoclonal antibody exhibits in vivo efficacy against both human metapneumovirus and respiratory syncytial virus. J. Infect. Dis. 211, 216–225 (2015).

    Article  CAS  Google Scholar 

  12. Jardetzky, T. S. & Lamb, R. A. Activation of paramyxovirus membrane fusion and virus entry. Curr. Opin. Virol. 5, 24–33 (2014).

    Article  CAS  Google Scholar 

  13. Wen, X. et al. Structure of the human metapneumovirus fusion protein with neutralizing antibody identifies a pneumovirus antigenic site. Nat. Struct. Mol. Biol. 19, 461–463 (2012).

    Article  CAS  Google Scholar 

  14. McLellan, J. S. et al. Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science 340, 1113–1117 (2013).

    Article  CAS  Google Scholar 

  15. McLellan, J. S., Yang, Y., Graham, B. S. & Kwong, P. D. Structure of the respiratory syncytial virus fusion glycoprotein in the post-fusion conformation reveals preservation of neutralizing epitopes. J. Virol. 85, 7788–7796 (2011).

    Article  CAS  Google Scholar 

  16. Swanson, K. A. et al. Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers. Proc. Natl Acad. Sci. USA 108, 9619–9624 (2011).

    Article  CAS  Google Scholar 

  17. Yin, H. S., Wen, X., Paterson, R. G., Lamb, R. A. & Jardetzky, T. S. Structure of the parainfluenza virus 5 F protein in its metastable, prefusion conformation. Nature 439, 38–44 (2006).

    Article  CAS  Google Scholar 

  18. Mas, V. et al. Engineering, structure and immunogenicity of the human metapneumovirus F protein in the postfusion conformation. PLoS Pathogens 12, e1005859 (2016).

    Article  Google Scholar 

  19. Joyce, M. G. et al. Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV. Nat. Struct. Mol. Biol. 23, 811–820 (2016).

    Article  CAS  Google Scholar 

  20. Boyington, J. C. et al. Structure-based design of head-only fusion glycoprotein immunogens for respiratory syncytial virus. PLoS ONE 11, e0159709 (2016).

    Article  Google Scholar 

  21. Stewart-Jones, G. B. et al. A cysteine zipper stabilizes a pre-fusion F glycoprotein vaccine for respiratory syncytial virus. PLoS ONE 10, e0128779 (2015).

    Article  Google Scholar 

  22. McLellan, J. S. et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 342, 592–598 (2013).

    Article  CAS  Google Scholar 

  23. Wen, X. et al. A chimeric pneumovirus fusion protein carrying neutralizing epitopes of both MPV and RSV. PLoS ONE 11, e0155917 (2016).

    Article  Google Scholar 

  24. Gilman, M. S. et al. Characterization of a prefusion-specific antibody that recognizes a quaternary, cleavage-dependent epitope on the RSV fusion glycoprotein. PLoS Pathog. 11, e1005035 (2015).

    Article  Google Scholar 

  25. Lee, P. S. & Wilson, I. A. Structural characterization of viral epitopes recognized by broadly cross-reactive antibodies. Curr. Top. Microbiol. Immunol. 386, 323–341 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Doria-Rose, N. A. & Joyce, M. G. Strategies to guide the antibody affinity maturation process. Curr. Opin. Virol. 11, 137–147 (2015).

    Article  CAS  Google Scholar 

  27. Schmidt, A. G. et al. Viral receptor-binding site antibodies with diverse germline origins. Cell 161, 1026–1034 (2015).

    Article  CAS  Google Scholar 

  28. Zhou, T. et al. Structural repertoire of HIV-1-neutralizing antibodies targeting the CD4 supersite in 14 donors. Cell 161, 1280–1292 (2015).

    Article  CAS  Google Scholar 

  29. Storoni, L. C., McCoy, A. J. & Read, R. J. Likelihood-enhanced fast rotation functions. Acta Crystallogr. D 60, 432–438 (2004).

    Article  Google Scholar 

  30. Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994).

    Article  Google Scholar 

  31. Zwart, P. H. et al. Automated structure solution with the PHENIX suite. Methods Mol. Biol. 426, 419–435 (2008).

    Article  CAS  Google Scholar 

  32. Adams, P. D. et al. PHENIX: building new software for automated crystallographic structure determination. Acta Crystallogr. D 58, 1948–1954 (2002).

    Article  Google Scholar 

  33. Emsley, P. & Cowtan, K. COOT: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004).

    Article  Google Scholar 

  34. Smith, S. A. et al. Persistence of circulating memory B cell clones with potential for dengue virus disease enhancement for decades following infection. J. Virol. 86, 2665–2675 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge support from the members of the Jardetzky, Lamb and Crowe laboratories. This research was supported in part by National Institutes of Health research grants AI-23173 (to R.A.L.) and GM-61050 (to T.S.J.). R.A.L. is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Structural Biology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Xiaolin Wen & Theodore S. Jardetzky

  2. Vanderbilt Vaccine Center, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA

    Jarrod J. Mousa, John T. Bates & James E. Crowe Jr

  3. Howard Hughes Medical Institute, Northwestern University, Evanston, 60208-3500, Illinois, USA

    Robert A. Lamb

  4. Department of Molecular Biosciences, Northwestern University, Evanston, 60208-3500, Illinois, USA

    Robert A. Lamb

  5. Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA

    James E. Crowe Jr

  6. Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA

    James E. Crowe Jr

Authors
  1. Xiaolin Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jarrod J. Mousa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John T. Bates
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert A. Lamb
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. James E. Crowe Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Theodore S. Jardetzky
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

X.W., J.J.M., J.T.B., R.A.L., J.E.C. and T.S.J. conceived and designed the experiments. X.W., J.J.M. and J.T.B. performed the experiments. X.W., J.J.M., J.T.B., R.A.L., J.E.C. and T.S.J. analysed the data. X.W., J.J.M. and J.T.B. contributed reagents, materials and analysis tools. X.W., J.J.M., J.T.B., R.A.L., J.E.C. and T.S.J. wrote and edited the manuscript.

Corresponding author

Correspondence to Theodore S. Jardetzky.

Ethics declarations

Competing interests

One of the authors (J.E.C.) declares a competing interest. J.E.C. is a consultant to Compuvax and a member of the Scientific Advisory Board of Meissa Vaccines. The remaining authors declare no competing interests.

Supplementary information

Supplementary Information

Supplementary Figures 1–7; Supplementary Tables 1 and 2; Supplementary References. (PDF 2668 kb)

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wen, X., Mousa, J., Bates, J. et al. Structural basis for antibody cross-neutralization of respiratory syncytial virus and human metapneumovirus. Nat Microbiol 2, 16272 (2017). https://doi.org/10.1038/nmicrobiol.2016.272

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/nmicrobiol.2016.272

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing