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

Abstract

Our resistance to infection is critically dependent upon the ability of pattern recognition receptors to recognise microbial invasion and induce protective immune responses. One such family of receptors are the C-type lectins, which play central roles in 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, including melanin2,3, whose mechanisms of recognition remain largely undefined. Here we identify a C-type lectin receptor, Melanin sensing C-type Lectin receptor (MelLec), that plays an essential role in antifungal immunity through recognition of the naphthalene-diol unit of 1,8-dihydroxynaphthalene (DHN)-melanin. MelLec recognises melanin in conidial spores of Aspergillus fumigatus, as well as other DHN-melanised fungi and is ubiquitously expressed by CD31+ endothelial cells in mice. MelLec is also expressed by a sub-population of these cells in mice that co-express EpCAM and which were detected only in the lung and 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 susceptibility of stem-cell transplant recipients to disseminated Aspergillus infections. Thus MelLec is a receptor recognising an immunologically active component commonly found on fungi and plays an essential role in protective antifungal immunity in both mice and humans.

The Core Fucose on an IgG Antibody is an Endogenous Ligand of Dectin‐1

“…Interestingly, a melanin‐sensing C‐type lectin receptor (MelLec) has been discovered recently in mammals. It has an essential role in antifungal immunity through recognition of the naphthalene‐diol unit of fungal melanin; this breakthrough further substantiates our finding of carbohydrate binding lectins also binding with aromatic residues.…”

Flotillin-dependent lipid-raft microdomains are required for functional phagolysosomes against fungal infections

“…Therefore, we next explored the role of this pathway in humans. We screened for single nucleotide polymorphisms (SNPs) and their association with the risk of invasive aspergillosis (IA) in a cohort of hematopoietic stem-cell transplant (HSCT) recipients (Stappers, Clark et al, 2018). Whereas for the FLOT2 gene there was no SNP associated with risk of infection, remarkably, rs3094127, a SNP (T>C) in the last intron of the FLOT1 gene that is lacking in the corresponding FLOT1 gene in mice ( Fig.…”

“…A total of 370 hematologic patients undergoing allogeneic hematopoietic stem-cell transplantation at the Hospital of Santa Maria, Lisbon and Instituto Português de Oncologia (IPO), Porto, between 2009 and 2014 were enrolled in the study (Stappers et al, 2018),…”

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

“…Inhaled dormant conidia of A. fumigatus that escape mucociliary clearance can reach the lung alveoli, where they are faced both by epithelial and innate immune cells (see 'Introduction'). However, recognition of conidia by cell-associated PRRs (e.g., dectin-1 [37] and dectin-2 [38], dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin, DC-SIGN [39], melanin-sensing C-type lectin receptor [40], and Tolllike receptors (TLR)2 and TLR4 [41]) is hampered by the rodlet and, possibly, melanin layers of the outer cell wall that mask the PAMPs (i.e., mostly polysaccharides) present in the inner cell wall [42,43]. Despite of this shielding effect, dormant conidia are phagocytosed and killed, which highlights the crucial role of soluble PRMs, including the complement system, in the early immune response to this opportunistic pathogen [23].…”