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

Mark Stappers (1) , Alexandra Clark (1) , Vishukumar Aimanianda (2) , Stefan Bidula (1) , Delyth Reid (1) , Patawee Asamaphan (1) , Sarah Hardison (1) , Ivy Dambuza (1) , Isabel Valsecchi (2) , Bernhard Kerscher (2) , Anthony Plato (1) , Carol Wallace (1) , Raif Yuecel (1) , Betty Hebecker (1) , Maria da Glória Teixeira Sousa (1) , Cristina Cunha (3) , Yan Liu (4) , Ten Feizi (4) , Axel Brakhage (5) , Kyung Kwon-Chung (6) , Neil A Gow (1) , Matteo Zanda (1) , Monica Piras (1) , Chiara Zanato (1) , Martin Jaeger (7) , Mihai G. Netea (7) , Frank van de Veerdonk (7) , João Lacerda (8) , Antonio Campos (9) , Agostinho Carvalho (3) , Janet Willment (1) , Jean-Paul Latgé (2) , Gordon D Brown (1)

1 University of Aberdeen
2 Aspergillus
3 Universidade do Minho = University of Minho [Braga]
4 Imperial College London
5 Leibniz Institute for Natural Product Research and Infection Biology (Hans Knoell Institute)
6 NIH - National Institutes of Health [Bethesda, MD, USA]
7 Radboud University Medical Center [Nijmegen]
8 ULISBOA - Universidade de Lisboa = University of Lisbon
9 IPO Porto - Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto

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.

Domaines: Sciences du Vivant [q-bio]; Immunologie; Immunité innée

Mark Stappers, Alexandra Clark, Vishukumar Aimanianda, Stefan Bidula, Delyth Reid, et al.. Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus. Nature, 2018, 555 (7696), pp.382-386. ⟨10.1038/nature25974⟩. ⟨pasteur-02501369⟩