2. Academic Validation
  3. Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus

Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus

  • Nature. 2018 Mar 15;555(7696):382-386. doi: 10.1038/nature25974.
Mark H T Stappers 1,  Alexandra E Clark 1,  Vishukumar Aimanianda 2,  Stefan Bidula 1,  Delyth M Reid 1,  Patawee Asamaphan 1,  Sarah E Hardison 1,  Ivy M Dambuza 1,  Isabel Valsecchi 2,  Bernhard Kerscher 1,  Anthony Plato 1,  Carol A Wallace 1,  Raif Yuecel 3,  Betty Hebecker 1,  Maria da Glória Teixeira Sousa 1,  Cristina Cunha 4 5,  Yan Liu 6,  Ten Feizi 6,  Axel A Brakhage 7,  Kyung J Kwon-Chung 8,  Neil A R Gow 1,  Matteo Zanda 9,  Monica Piras 9,  Chiara Zanato 9,  Martin Jaeger 10,  Mihai G Netea 10,  Frank L van de Veerdonk 10,  João F Lacerda 11 12,  António Campos 13,  Agostinho Carvalho 4 5,  Janet A Willment 1,  Jean-Paul Latgé 2,  Gordon D Brown 1
Affiliations

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.
  • 2 Unité des Aspergillus, Institut Pasteur, Paris, France.
  • 3 Iain Fraser Cytometry Centre, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
  • 4 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
  • 5 ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
  • 6 Glycosciences Laboratory, Department of Medicine, Imperial College London, London W12 0NN, UK.
  • 7 Department of Microbiology and Molecular Biology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Friedrich Schiller University, D-07745 Jena, Germany.
  • 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.
  • 9 Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
  • 10 Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 11 Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal.
  • 12 Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Lisboa, Portugal.
  • 13 Serviço de Transplantação de Medula Óssea (STMO), Instituto Português de Oncologia do Porto, Porto, Portugal.
PMID: 29489751 DOI: 10.1038/nature25974
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 immunity. 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 melanin, 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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