Abstract

Resistance to infection is critically dependent on the ability of pattern recognition receptors to recognize microbial invasion and induce protective immune responses. One such family of receptors are the C-type lectins, which are central to antifungal immunity1. These receptors activate key effector mechanisms upon recognition of conserved fungal cell-wall carbohydrates. However, several other immunologically active fungal ligands have been described; these include melanin2,3, for which the mechanism of recognition is hitherto undefined. Here we identify a C-type lectin receptor, melanin-sensing C-type lectin receptor (MelLec), that has an essential role in antifungal immunity through recognition of the naphthalene-diol unit of 1,8-dihydroxynaphthalene (DHN)-melanin. MelLec recognizes melanin in conidial spores of Aspergillus fumigatus as well as in other DHN-melanized fungi. MelLec is ubiquitously expressed by CD31+ endothelial cells in mice, and is also expressed by a sub-population of these cells that co-express epithelial cell adhesion molecule and are detected only in the lung and the liver. In mouse models, MelLec was required for protection against disseminated infection with A. fumigatus. In humans, MelLec is also expressed by myeloid cells, and we identified a single nucleotide polymorphism of this receptor that negatively affected myeloid inflammatory responses and significantly increased the susceptibility of stem-cell transplant recipients to disseminated Aspergillus infections. MelLec therefore recognizes an immunologically active component commonly found on fungi and has an essential role in protective antifungal immunity in both mice and humans.

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Acknowledgements

We thank the staff of the University of Aberdeen animal facility for their support and care for our animals, C. G. Park for providing recombinant langerin, and S. Filler and R. Cramer for advice. Funding was provided by the Wellcome Trust (102705, 097377, 093378, 099197, 108430, 101873), the Medical Research Council Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1). K.J.K.-C is supported by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; V.A. by an ANR-DST COMASPIN grant (ANR-13-ISV3-0004); B.H. by German Science Foundation (www.dfg.de) grant no. HE 7565/1-1; J.-P.L., I.V. and V.A. by the ANR and FRM DEQ2015-331722; A.C. by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), and by the Fundação para a Ciência e Tecnologia (FCT) (IF/00735/2014 and SFRH/BPD/96176/2013).

Author information

Author notes

    • Jean-Paul Latgé

    Present address: State Key Laboratory, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

    • Mark H. T. Stappers
    • , Alexandra E. Clark
    •  & Vishukumar Aimanianda

    These authors contributed equally to this work.

Affiliations

  1. Medical Research Council Centre for Medical Mycology at the University of Aberdeen, Aberdeen Fungal Group, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK

    • Mark H. T. Stappers
    • , Alexandra E. Clark
    • , Stefan Bidula
    • , Delyth M. Reid
    • , Patawee Asamaphan
    • , Sarah E. Hardison
    • , Ivy M. Dambuza
    • , Bernhard Kerscher
    • , Anthony Plato
    • , Carol A. Wallace
    • , Betty Hebecker
    • , Maria da Glória Teixeira Sousa
    • , Neil A. R. Gow
    • , Janet A. Willment
    •  & Gordon D. Brown
  2. Unité des Aspergillus, Institut Pasteur, Paris, France

    • Vishukumar Aimanianda
    • , Isabel Valsecchi
    •  & Jean-Paul Latgé
  3. Iain Fraser Cytometry Centre, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK

    • Raif Yuecel
  4. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal

    • Cristina Cunha
    •  & Agostinho Carvalho
  5. ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal

    • Cristina Cunha
    •  & Agostinho Carvalho
  6. Glycosciences Laboratory, Department of Medicine, Imperial College London, London W12 0NN, UK

    • Yan Liu
    •  & Ten Feizi
  7. Department of Microbiology and Molecular Biology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Friedrich Schiller University, D-07745 Jena, Germany

    • Axel A. Brakhage
  8. Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA

    • Kyung J. Kwon-Chung
  9. Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK

    • Matteo Zanda
    • , Monica Piras
    •  & Chiara Zanato
  10. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

    • Martin Jaeger
    • , Mihai G. Netea
    •  & Frank L. van de Veerdonk
  11. Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal

    • João F. Lacerda
  12. Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Lisboa, Portugal

    • João F. Lacerda
  13. Serviço de Transplantação de Medula Óssea (STMO), Instituto Português de Oncologia do Porto, Porto, Portugal

    • António Campos

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Contributions

G.D.B., J.-P.L. and J.A.W. conceived and designed the study and guided the interpretation of the results. A.E.C., M.H.T.S. and V.A. performed the majority of the experiments and data analysis. S.B., D.M.R., P.A., S.E.H., I.M.D., B.K., A.P., J.A.W., C.C., M.d.G.T.S., C.A.W., R.Y. and B.H. conducted experiments and data analysis. Y.L. and T.F. performed the glycan microarray experiments and data analysis. M.J., M.G.N., F.L.v.d.V., J.F.L., A.Cam. and A.Car. provided the human patient data and analysis. A.A.B., K.J.K.-C., I.V., M.P., C.Z., M.Z. and N.A.R.G. provided critical conceptual input and reagents. G.D.B. drafted the manuscript. All authors discussed the results, edited and approved the draft and final versions of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Gordon D. Brown.

Reviewer Information Nature thanks A. Casadevall, C. Reis e Sousa and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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

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