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

Publication . Stappers, Mark H. T.; Clark, Alexandra E.; Aimanianda, Vishukumar; Bidula, Stefan; Reid, Delyth M.; Asamaphan, Patawee; Hardison, Sarah E.; Dambuza, Ivy M.; Valsecchi, Isabel; Kerscher, Bernhard; Plato, Anthony; Wallace, Carol A.; Yuecel, Raif; Hebecker, Betty; da Glória Teixeira Sousa, Maria; Cunha, Cristina; Liu, Yan; Feizi, Ten; Brakhage, Axel A.; Kwon-Chung, Kyung J.; Gow, Neil A. R.; Zanda, Matteo; Piras, Monica; Zanato, Chiara; Jaeger, Martin; Netea, Mihai G.; van de Veerdonk, Frank L.; Lacerda, João; Campos, António; Carvalho, Agostinho; Willment, Janet A.; Latgé, Jean-Paul; Brown, Gordon D.

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.

2018Journal article

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The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells

Publication . Chorny, Alejo; Casas-Recasens, Sandra; Sintes, Jordi; Shan, Meimei; Polentarutti, Nadia; García-Escudero, Ramón; Walland, A. Cooper; Yeiser, John R.; Cassis, Linda; Carrillo, Jorge; Puga, Irene; Cunha, Cristina; Bastos, Hélder; Rodrigues, Fernando; Lacerda, João; Morais, António; Dieguez-Gonzalez, Rebeca; Heeger, Peter S.; Salvatori, Giovanni; Carvalho, Agostinho; Garcia-Sastre, Adolfo; Blander, J. Magarian; Mantovani, Alberto; Garlanda, Cecilia; Cerutti, Andrea

Pentraxin 3 (PTX3) is a fluid-phase pattern recognition receptor of the humoral innate immune system with ancestral antibody-like properties but unknown antibody-inducing function. In this study, we found binding of PTX3 to splenic marginal zone (MZ) B cells, an innate-like subset of antibody-producing lymphocytes strategically positioned at the interface between the circulation and the adaptive immune system. PTX3 was released by a subset of neutrophils that surrounded the splenic MZ and expressed an immune activation-related gene signature distinct from that of circulating neutrophils. Binding of PTX3 promoted homeostatic production of IgM and class-switched IgG antibodies to microbial capsular polysaccharides, which decreased in PTX3-deficient mice and humans. In addition, PTX3 increased IgM and IgG production after infection with blood-borne encapsulated bacteria or immunization with bacterial carbohydrates. This immunogenic effect stemmed from the activation of MZ B cells through a neutrophil-regulated pathway that elicited class switching and plasmablast expansion via a combination of T cell-independent and T cell-dependent signals. Thus, PTX3 may bridge the humoral arms of the innate and adaptive immune systems by serving as an endogenous adjuvant for MZ B cells. This property could be harnessed to develop more effective vaccines against encapsulated pathogens.

2016Journal article

Open access

Calcium sequestration by fungal melanin inhibits calcium–calmodulin signalling to prevent LC3-associated phagocytosis

Publication . Kyrmizi, Irene; Ferreira, Helena; Carvalho, Agostinho; Figueroa, Julio Alberto Landero; Zarmpas, Pavlos; Cunha, Cristina; Akoumianaki, Tonia; Stylianou, Kostas; Deepe, George S.; Samonis, George; Lacerda, João; Campos, António; Kontoyiannis, Dimitrios P.; Mihalopoulos, Nikolaos; Kwon-Chung, Kyung J.; El-Benna, Jamel; Valsecchi, Isabel; Beauvais, Anne; Brakhage, Axel A.; Neves, Nuno M.; Latge, Jean-Paul; Chamilos, Georgios

LC3-associated phagocytosis (LAP) is a non-canonical autophagy pathway regulated by Rubicon, with an emerging role in immune homeostasis and antifungal host defence. Aspergillus cell wall melanin protects conidia (spores) from killing by phagocytes and promotes pathogenicity through blocking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent activation of LAP. However, the signalling regulating LAP upstream of Rubicon and the mechanism of melanin-induced inhibition of this pathway remain incompletely understood. Herein, we identify a Ca2+ signalling pathway that depends on intracellular Ca2+ sources from endoplasmic reticulum, endoplasmic reticulum-phagosome communication, Ca2+ release from phagosome lumen and calmodulin (CaM) recruitment, as a master regulator of Rubicon, the phagocyte NADPH oxidase NOX2 and other molecular components of LAP. Furthermore, we provide genetic evidence for the physiological importance of Ca2+-CaM signalling in aspergillosis. Finally, we demonstrate that Ca2+ sequestration by Aspergillus melanin inside the phagosome abrogates activation of Ca2+-CaM signalling to inhibit LAP. These findings reveal the important role of Ca2+-CaM signalling in antifungal immunity and identify an immunological function of Ca2+ binding by melanin pigments with broad physiological implications beyond fungal disease pathogenesis.

2018Journal article

Restricted access