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.

  • Article
  • Published:

Human CD45 is an F-component-specific receptor for the staphylococcal toxin Panton–Valentine leukocidin

Nature Microbiology volume 3, pages 708–717 (2018)Cite this article

Subjects

A Publisher Correction to this article was published on 03 September 2018

This article has been updated

Abstract

The staphylococcal bi-component leukocidins Panton–Valentine leukocidin (PVL) and γ-haemolysin CB (HlgCB) target human phagocytes. Binding of the toxins’ S-components to human complement C5a receptor 1 (C5aR1) contributes to cellular tropism and human specificity of PVL and HlgCB. To investigate the role of both leukocidins during infection, we developed a human C5aR1 knock-in (hC5aR1KI) mouse model. HlgCB, but unexpectedly not PVL, contributed to increased bacterial loads in tissues of hC5aR1KI mice. Compared to humans, murine hC5aR1KI neutrophils showed a reduced sensitivity to PVL, which was mediated by the toxin’s F-component LukF-PV. By performing a genome-wide CRISPR–Cas9 screen, we identified CD45 as a receptor for LukF-PV. The human-specific interaction between LukF-PV and CD45 provides a molecular explanation for resistance of hC5aR1KI mouse neutrophils to PVL and probably contributes to the lack of a PVL-mediated phenotype during infection in these mice. This study demonstrates an unsuspected role of the F-component in driving the sensitivity of human phagocytes to PVL.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: hC5aR1 and HlgCB, but not PVL, contribute to increased bacterial loads in hC5aR1KI mice.
Fig. 2: PVL and HlgCB differentially target hC5aR1KI murine neutrophils in an F-component-specific manner.
Fig. 3: PVL targets CD45.
Fig. 4: PVL targets CD45 in an F-component-specific manner.
Fig. 5: PVL targets CD45 in a human-specific manner.

Similar content being viewed by others

Change history

  • 03 September 2018

    In the version of this Article originally published, the name of author Robert Jan Lebbink was coded wrongly, resulting in it being incorrect when exported to citation databases. This has now been corrected, though no visible changes will be apparent.

References

  1. Thwaites, G. E. et al. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect. Dis. 11, 208–222 (2011).

    Article  PubMed  Google Scholar 

  2. Deleo, F. R., Otto, M., Kreiswirth, B. N. & Chambers, H. F. Community-associated meticillin-resistant Staphylococcus aureus. Lancet 375, 1557–1568 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fowler, V. G. et al. Effect of an investigational vaccine for preventing Staphylococcus aureus infections after cardiothoracic surgery: a randomized trial. JAMA 309, 1368–1378 (2013).

    Article  PubMed  CAS  Google Scholar 

  4. Spaan, A. N., Surewaard, B. G., Nijland, R. & van Strijp, J. A. Neutrophils versus Staphylococcus aureus: a biological tug of war. Annu. Rev. Microbiol. 67, 629–650 (2013).

    Article  PubMed  CAS  Google Scholar 

  5. Alonzo, F. III. & Torres, V. J. The bicomponent pore-forming leucocidins of Staphylococcus aureus. Microbiol. Mol. Biol. Rev. 78, 199–230 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Vandenesch, F., Lina, G. & Henry, T. Staphylococcus aureus hemolysins, bi-component leukocidins, and cytolytic peptides: a redundant arsenal of membrane-damaging virulence factors? Front. Cell Infect. Microbiol. 2, 12 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Spaan, A. N., van Strijp, J. A. G. & Torres, V. J. Leukocidins: staphylococcal bi-component pore-forming toxins find their receptors. Nat. Rev. Microbiol. 15, 435–447 2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Peraro, M. D. & van der Goot, F. G. Pore-forming toxins: ancient, but never really out of fashion. Nat. Rev. Microbiol. 14, 77–92 (2016).

    Article  CAS  Google Scholar 

  9. Ferreras, M. et al. The interaction of Staphylococcus aureus bi-component γ-hemolysins and leucocidins with cells and lipid membranes. Biochim. Biophys. Acta 1414, 108–126 (1998).

    Article  PubMed  CAS  Google Scholar 

  10. Dalla Serra, M. et al. Staphylococcus aureus bicomponent γ-hemolysins, HlgA, HlgB, and HlgC, can form mixed pores containing all components. J. Chem. Inf. Model. 45, 1539–1545 (2005).

    Article  PubMed  CAS  Google Scholar 

  11. Konig, B., Prevost, G. & Konig, W. Composition of staphylococcal bi-component toxins determines pathophysiological reactions. J. Med. Microbiol. 46, 479–485 (1997).

    Article  PubMed  CAS  Google Scholar 

  12. Yoong, P. & Torres, V. J. Counter inhibition between leukotoxins attenuates Staphylococcus aureus virulence. Nat. Commun. 6, 8125 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  13. DuMont, A. L. et al. Staphylococcus aureus LukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1. Proc. Natl Acad. Sci. USA 110, 10794–10799 (2013).

    Article  PubMed  Google Scholar 

  14. Spaan, A. N. et al. The staphylococcal toxin Panton–Valentine leukocidin targets human C5a receptors. Cell Host Microbe 13, 584–594 2013).

    Article  PubMed  CAS  Google Scholar 

  15. Reyes-Robles, T. et al. Staphylococcus aureus leukotoxin ED targets the chemokine receptors CXCR1 and CXCR2 to kill leukocytes and promote infection. Cell Host Microbe 14, 453–459 (2013).

    Article  PubMed  CAS  Google Scholar 

  16. Spaan, A. N. et al. The staphylococcal toxins γ-haemolysin AB and CB differentially target phagocytes by employing specific chemokine receptors. Nat. Commun. 5, 5438 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Koop, G. et al. Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus. Sci. Rep. 7, 40660 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Spaan, A. N. et al. Staphylococcus aureus targets the Duffy antigen receptor for chemokines (DARC) to lyse erythrocytes. Cell Host Microbe 18, 363–370 2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Vrieling, M. et al. Bovine Staphylococcus aureus secretes the leukocidin LukMF’ to kill migrating neutrophils through CCR1. mBio 6, e00335 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Alonzo, F. III. et al. CCR5 is a receptor for Staphylococcus aureus leukotoxin ED. Nature 493, 51–55 (2013).

    Article  PubMed  CAS  Google Scholar 

  21. Spaan, A. N. et al. Differential interaction of the staphylococcal toxins Panton–Valentine leukocidin and γ-hemolysin CB with human C5a receptors. J. Immunol. 195, 1034–1043 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Tawk, M. Y. et al. Internalization of staphylococcal leukotoxins that bind and divert the C5a receptor is required for intracellular Ca2+ mobilization by human neutrophils. Cell. Microbiol. 17, 1241–1257 (2015).

    Article  PubMed  CAS  Google Scholar 

  23. Labandeira-Rey, M. et al. Staphylococcus aureus Panton–Valentine leukocidin causes necrotizing pneumonia. Science 315, 1130–1133 (2007).

    Article  PubMed  CAS  Google Scholar 

  24. Bubeck Wardenburg, J., Bae, T., Otto, M., Deleo, F. R. & Schneewind, O. Poring over pores: α-hemolysin and Panton–Valentine leukocidin in Staphylococcus aureus pneumonia. Nat. Med. 13, 1405–1406 (2007).

    Article  PubMed  CAS  Google Scholar 

  25. Diep, B. A. et al. Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton–Valentine leukocidin-induced lung inflammation and injury. Proc. Natl Acad. Sci. USA 107, 5587–5592 (2010).

    Article  PubMed  CAS  Google Scholar 

  26. Cremieux, A. C. et al. Panton–Valentine leukocidin enhances the severity of community-associated methicillin-resistant Staphylococcus aureus rabbit osteomyelitis. PLoS ONE 4, e7204 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Diep, B. A. et al. Contribution of Panton–Valentine leukocidin in community-associated methicillin-resistant Staphylococcus aureus pathogenesis. PLoS ONE 3, e3198 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Lipinska, U. et al. Panton–Valentine leukocidin does play a role in the early stage of Staphylococcus aureus skin infections: a rabbit model. PLoS ONE 6, e22864 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Kobayashi, S. D. et al. Comparative analysis of USA300 virulence determinants in a rabbit model of skin and soft tissue infection. J. Infect. Dis. 204, 937–941 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Shallcross, L. J., Fragaszy, E., Johnson, A. M., & Hayward, A. C. The role of the Panton-Valentine leucocidin toxin in staphylococcal disease: a systematic review and meta-analysis. Lancet Infect. Dis. 13, 43–54 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Tseng, C. W. et al. Increased susceptibility of humanized NSG mice to Panton–Valentine leukocidin and Staphylococcus aureus skin infection. PLoS Pathog. 11, e1005292 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Prince, A., Wang, H., Kitur, K. & Parker, D. Humanized mice exhibit increased susceptibility to Staphylococcus aureus pneumonia. J. Infect. Dis. 215, 1386–1395 (2017).

    PubMed  Google Scholar 

  33. Monk, P. N., Scola, A. M., Madala, P. & Fairlie, D. P. Function, structure and therapeutic potential of complement C5a receptors. Br. J. Pharmacol. 152, 429–448 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Otter, J. A. & French, G. L. Molecular epidemiology of community-associated meticillin-resistant Staphylococcus aureus in Europe. Lancet Infect. Dis. 10, 227–239 (2010).

    Article  PubMed  Google Scholar 

  35. Hermiston, M. L., Xu, Z. & Weiss, A. CD45: a critical regulator of signaling thresholds in immune cells. Annu. Rev. Immunol. 21, 107–137 (2003).

    Article  PubMed  CAS  Google Scholar 

  36. Lowy, F. D. Staphylococcus aureus infections. N. Engl. J. Med. 339, 520–532 1998).

    Article  PubMed  CAS  Google Scholar 

  37. Gillet, Y. et al. Association between Staphylococcus aureus strains carrying gene for Panton–Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 359, 753–759 (2002).

    Article  PubMed  CAS  Google Scholar 

  38. Alcais, A., Abel, L. & Casanova, J. L. Human genetics of infectious diseases: between proof of principle and paradigm. J. Clin. Invest. 119, 2506–2514 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Casanova, J. L. Severe infectious diseases of childhood as monogenic inborn errors of immunity. Proc. Natl Acad. Sci. USA 112, E7128–E7137 (2015).

    PubMed  CAS  Google Scholar 

  40. Kung, C. et al. Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat. Med. 6, 343–345 (2000).

    Article  PubMed  CAS  Google Scholar 

  41. Tchilian, E. Z. et al. A deletion in the gene encoding the CD45 antigen in a patient with SCID. J. Immunol. 166, 1308–1313 (2001).

    Article  PubMed  CAS  Google Scholar 

  42. Tchilian, E. Z. et al. The exon A (C77G) mutation is a common cause of abnormal CD45 splicing in humans. J. Immunol. 166, 6144–6148 (2001).

    Article  PubMed  CAS  Google Scholar 

  43. Lee, H. et al. Human C5aR knock-in mice facilitate the production and assessment of anti-inflammatory monoclonal antibodies. Nat. Biotechnol. 24, 1279–1284(2006).

    Article  PubMed  CAS  Google Scholar 

  44. Birling, M. C., Dierich, A., Jacquot, S., Herault, Y. & Pavlovic, G. Highly-efficient, fluorescent, locus directed cre and FlpO deleter mice on a pure C57BL/6N genetic background. Genesis 50, 482–489 (2012).

    Article  PubMed  CAS  Google Scholar 

  45. van de Weijer, M. L. et al. A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation. Nat. Commun. 5, 3832 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. van Diemen, F. R. et al. CRISPR/Cas9-mediated genome editing of herpesviruses limits productive and latent infections. PLoS Pathog. 12, e1005701 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Blasi, E. et al. Selective immortalization of murine macrophages from fresh bone marrow by a raf/myc recombinant murine retrovirus. Nature 318, 667–670 (1985).

    Article  PubMed  CAS  Google Scholar 

  48. Perret, M. et al. Cross-talk between S. aureus leukocidins-intoxicated macrophages and lung epithelial cells triggers chemokine secretion in an inflammasome-dependent manner. Cell. Microbiol. 14, 1019–1036 (2012).

    Article  PubMed  CAS  Google Scholar 

  49. Garnier, F. et al. Pneumonia and new methicillin-resistant Staphylococcus aureus clone. Emerg. Infect. Dis. 12, 498–500 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Gauduchon, V., Werner, S., Prevost, G., Monteil, H. & Colin, D. A. Flow cytometric determination of Panton–Valentine leucocidin S component binding. Infect. Immun. 69, 2390–2395 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Meyer, F., Girardot, R., Piemont, Y., Prevost, G. & Colin, D. A. Analysis of the specificity of Panton–Valentine leucocidin and gamma-hemolysin F component binding. Infect. Immun. 77, 266–273 (2009).

    Article  PubMed  CAS  Google Scholar 

  52. Mubaiwa, T. D. et al. The glycointeractome of serogroup B Neisseria meningitidis strain MC58. Sci. Rep. 7, 5693 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We thank L. Scheepmaker and P. C. Aerts (University Medical Center Utrecht, Utrecht, The Netherlands) for technical support, C. Badiou (CIRI Inserm U111, Lyon, France) and G. Prevost (Strasbourg University, Strasbourg, France) for providing toxins and Y. Benito (CIRI Inserm U111) for providing S. aureus strains; PBES (J. F. Henry), lentivectors production facility (C. Costa) and flow cytometry platforms of SFR Biosciences Gerland—Lyon Sud. This work is supported by grants from the Agence Nationale de la Recherche (ANR-12-BSV3-0003 to F.V. and T.H.), the Finovi foundation (to T.H.), the Australian National Health and Medical Research Council (1071659 and 1138466 to M.P.J. and 1108124 to M.P.J. and C.J.D.) and the Dutch Cancer Society (UU 2012-5667 to R.J.L.). This work was performed within the framework of LABEX ECOFECT (ANR-11−LABX-0048) of Université de Lyon and ANR ‘Investissements d’Avenir’ (ANR-11-IDEX-0007).

Author information

Author notes

  1. These authors contributed equally: Angelino T. Tromp, Michiel Van Gent.

  2. These authors jointly supervised this work: Thomas Henry, András N. Spaan.

Authors and Affiliations

  1. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands

    Angelino T. Tromp, Michiel Van Gent, Joris P. Jansen, Carla J. C. De Haas, Kok P. M. Van Kessel, Bart W. Bardoel, Elisabeth Kruse, Jos A. G. Van Strijp, Robert Jan Lebbink, Pieter-Jan A. Haas & András N. Spaan

  2. Department of Microbiology, University of Chicago, Chicago, IL, USA

    Michiel Van Gent

  3. CIRI, Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, Hospices Civils de Lyon, Lyon, France

    Pauline Abrial, Amandine Martin, Emilie Bourdonnay, Gérard Lina, François Vandenesch & Thomas Henry

  4. Department of Microbiology and Immunology, UCSF Diabetes Center, Keck Center for Noncoding RNA, University of California, San Francisco, San Francisco, CA, USA

    Michael Boettcher & Michael T. McManus

  5. Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia

    Christopher J. Day & Michael P. Jennings

  6. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    András N. Spaan

Authors
  1. Angelino T. Tromp
    View author publications

    Search author on:PubMed Google Scholar

  2. Michiel Van Gent
    View author publications

    Search author on:PubMed Google Scholar

  3. Pauline Abrial
    View author publications

    Search author on:PubMed Google Scholar

  4. Amandine Martin
    View author publications

    Search author on:PubMed Google Scholar

  5. Joris P. Jansen
    View author publications

    Search author on:PubMed Google Scholar

  6. Carla J. C. De Haas
    View author publications

    Search author on:PubMed Google Scholar

  7. Kok P. M. Van Kessel
    View author publications

    Search author on:PubMed Google Scholar

  8. Bart W. Bardoel
    View author publications

    Search author on:PubMed Google Scholar

  9. Elisabeth Kruse
    View author publications

    Search author on:PubMed Google Scholar

  10. Emilie Bourdonnay
    View author publications

    Search author on:PubMed Google Scholar

  11. Michael Boettcher
    View author publications

    Search author on:PubMed Google Scholar

  12. Michael T. McManus
    View author publications

    Search author on:PubMed Google Scholar

  13. Christopher J. Day
    View author publications

    Search author on:PubMed Google Scholar

  14. Michael P. Jennings
    View author publications

    Search author on:PubMed Google Scholar

  15. Gérard Lina
    View author publications

    Search author on:PubMed Google Scholar

  16. François Vandenesch
    View author publications

    Search author on:PubMed Google Scholar

  17. Jos A. G. Van Strijp
    View author publications

    Search author on:PubMed Google Scholar

  18. Robert Jan Lebbink
    View author publications

    Search author on:PubMed Google Scholar

  19. Pieter-Jan A. Haas
    View author publications

    Search author on:PubMed Google Scholar

  20. Thomas Henry
    View author publications

    Search author on:PubMed Google Scholar

  21. András N. Spaan
    View author publications

    Search author on:PubMed Google Scholar

Contributions

A.T.T., M.V.G., B.W.B., F.V., T.H. and A.N.S. conceptualized the study. A.T.T., M.V.G., R.J.L., P.-J.A.H., K.P.M.V.K., C.J.D., M.P.J., T.H. and A.N.S. designed the methodology. A.T.T., M.V.G., P.A., A.M., J.P.J., C.J.C.D.H., E.B., C.J.D., T.H. and A.N.S. conducted the investigation. E.K., C.J.C.D.H., M.B., C.J.D., M.P.J. and M.T.M. provided resources. G.L., F.V., J.A.G.V.S., P.-J.A.H. and T.H. provided funding. A.T.T., M.V.G., T.H. and A.N.S. wrote the paper. R.J.L., P.-J.A.H., T.H. and A.N.S. provided supervision.

Corresponding authors

Correspondence to Thomas Henry or András N. Spaan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figures 1–6.

Reporting Summary

Supplementary Table 1

Screening results for resistance to PVL toxicity.

Supplementary Table 2

Selected sgRNAs for a genome-wide library.

Supplementary Table 3

Exact P values.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tromp, A.T., Van Gent, M., Abrial, P. et al. Human CD45 is an F-component-specific receptor for the staphylococcal toxin Panton–Valentine leukocidin. Nat Microbiol 3, 708–717 (2018). https://doi.org/10.1038/s41564-018-0159-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41564-018-0159-x

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