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

Abstract

The C-type lectin receptor MelLec recognizes DHN-melanin in conidial spores of Aspergillus fumigatus and other DHN-melanized fungi, revealing an important role for this receptor in antifungal immunity in both mice and humans. Defence against fungal pathogens in mammals relies on pattern recognition receptors, which are often activated by pathogen virulence factors. One such factor is melanin, a component of the fungal cell wall. Gordon Brown and colleagues identify the melanin-sensing C-type lectin receptor (MelLec) as an endothelial cell receptor for fungal melanin. Activation of this receptor triggers a protective inflammatory response against infection by Aspergillus fungi in mice and humans. MelLec thereby has an important role in host defence against disseminated Aspergillosis. 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.