Abstract
Dihydroxynaphthalene melanin (DHN-melanin) is an integral component of the conidial cell wall surface, which has a central role in the pathogenicity of the major human airborne fungal pathogen Aspergillus fumigatus. Although the biosynthetic pathway for A. fumigatus DHN-melanin production has been well characterized, the molecular interactions of DHN-melanin with the immune system have been incompletely understood. Recent studies demonstrated that apart from concealing immunostimulatory cell wall polysaccharides, calcium sequestration by DHN-melanin inhibits essential host effector pathways regulating phagosome biogenesis and prevents A. fumigatus conidia killing by phagocytes. From the host perspective, DHN-melanin is specifically recognized by a C-type lectin receptor (MelLeC) present in murine endothelia and in human myeloid cells. Furthermore, DHN-melanin activates platelets and facilitates opsonophagocytosis by macrophages via binding to soluble pattern recognition receptors. Dissecting the dynamics of DHN-melanin organization on the fungal cell wall and the molecular interplay with the immune system will lead to a better understanding of A. fumigatus pathophysiology.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Aimanianda V, Bayry J, Bozza S, Kniemeyer O, Perruccio K, Elluru SR, Clavaud C, Paris S, Brakhage AA, Kaveri SV, Romani L, Latgé JP (2009) Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature 460(7259):1117–1121
Akoumianaki T, Kyrmizi I, Valsecchi I, Gresnigt MS, Samonis G, Drakos E, Boumpas D, Muszkieta L, Prevost MC, Kontoyiannis DP, Chavakis T, Netea MG, van de Veerdonk FL, Brakhage AA, El-Benna J, Beauvais A, Latge JP, Chamilos G (2016) Aspergillus cell wall melanin blocks LC3-associated phagocytosis to promote pathogenicity. Cell Host Microbe 19(1):79–90
Amin S, Thywissen A, Heinekamp T, Saluz HP, Brakhage AA (2014) Melanin dependent survival of Apergillus fumigatus conidia in lung epithelial cells. Int J MedMicrobiol 304(5–6):626–636
Bayry J, Beaussart A, Dufrêne YF, Sharma M, Bansal K, Kniemeyer O, Aimanianda V, Brakhage AA, Kaveri SV, Kwon-Chung KJ, Latgé JP, Beauvais A (2014) Surface structure characterization of Aspergillus fumigatus conidia mutated in the melanin synthesis pathway and their human cellular immune response. Infect Immun 82(8):3141–3153
Burkhart CG, Burkhart CN (2005) The mole theory: primary function of melanocytes and melanin may be antimicrobial defense and immunomodulation (not solar protection). Int J Dermatol 44(4):340–342
Camacho E, Vij R, Chrissian C, Prados-Rosales R, Gil D, O’Meally RN, Cordero RJB, Cole RN, McCaffery JM, Stark RE, Casadevall A (2019) The structural unit of melanin in the cell wall of the fungal pathogen Cryptococcus neoformans. J Biol Chem 294(27):10471–10489
Fogarty RV, Tobin JM (1996) Fungal melanins and their interactions with metals. Enzyme Microb Tech 19:311–317
Heinekamp T, Thywißen A, Macheleidt J, Keller S, Valiante V, Brakhage AA (2013) Aspergillus fumigatus melanins: interference with the host endocytosis pathway and impact on virulence. Front Microbiol 18(3):440
Jahn B, Koch A, Schmidt A, Wanner G, Gehringer H, Bhakdi S, Brakhage AA (1997) Isolation and characterization of a pigmentless-conidium mutant of Aspergillus fumigatus with altered conidial surface and reduced virulence. Infect Immun 65(12):5110–5117
Jahn B, Boukhallouk F, Lotz J, Langfelder K, Wanner G, Brakhage AA (2000) Interaction of human phagocytes with pigmentless Aspergillus conidia. Infect Immun 68(6):3736–3739
Jahn B, Langfelder K, Schneider U, Schindel C, Brakhage AA (2002) PKSP-dependent reduction of phagolysosome fusion and intracellular kill of Aspergillus fumigatus conidia by human monocyte-derived macrophages. Cell Microbiol 4(12):793–803
Jackson JC, Higgins LA, Lin X (2009) Conidiation color mutants of Aspergillus fumigatus are highly pathogenic to the heterologous insect host Galleria mellonella. PLoS ONE 4(1):e4224
Kang X, Kirui A, Muszyński A, Widanage MCD, Chen A, Azadi P, Wang P, Mentink-Vigier F, Wang T (2018) Molecular architecture of fungal cell walls revealed by solid-state NMR. Nat Commun 9(1):2747
Korytowski W, Sarna T (1990) Bleaching of melanin pigments. Role of copper ions and hydrogen peroxide in autooxidation and photooxidation of synthetic dopa-melanin. J Biol Chem 265(21):12410–12416
Kuo MJ, Alexander M (1967) Inhibition of the lysis of fungi by melanins. J Bacteriol 94(3):624–629
Kyrmizi I, Ferreira H, Carvalho A, Figueroa JAL, Zarmpas P, Cunha C, Akoumianaki T, Stylianou K, Deepe GS Jr, Samonis G, Lacerda JF, Campos A Jr, Kontoyiannis DP, Mihalopoulos N, Kwon-Chung KJ, El-Benna J, Valsecchi I, Beauvais A, Brakhage AA, Neves NM, Latge JP, Chamilos G (2018) Calcium sequestration by fungal melanin inhibits calcium-calmodulin signalling to prevent LC3-associated phagocytosis. Nat Microbiol 3(7):791–803
Langfelder K, Jahn B, Gehringer H, Schmidt A, Wanner G, Brakhage AA (1998) Identification of a polyketide synthase gene (pksP) of Aspergillus fumigatus involved in conidial pigment biosynthesis and virulence. Med Microbiol Immunol 187(2):79–89
Langfelder K, Streibel M, Jahn B, Haase G, Brakhage AA (2003) Biosynthesis of fungal melanins and their importance for human pathogenic fungi. Fungal Genet Biol 38(2):143–158
Lionakis MS, Lewis RE, May GS, Wiederhold NP, Albert ND, Halder G, Kontoyiannis DP (2005) Toll-deficient Drosophila flies as a fast, high-throughput model for the study of antifungal drug efficacy against invasive aspergillosis and Aspergillus virulence. J Infect Dis 191(7):1188–1195
Luther JP, Lipke H (1980) Degradation of melanin by Aspergillus fumigatus. Appl Environ Microbiol 40(1):145–155
Manfiolli AO, Siqueira FS, Dos Reis TF, Van Dijck P, Schrevens S, Hoefgen S, Föge M, Straßburger M, de Assis LJ, Heinekamp T, Rocha MC, Janevska S, Brakhage AA, Malavazi I, Goldman GH, Valiante V (2019) Mitogen-activated protein kinase cross-talk interaction modulates the production of melanins in Aspergillus fumigatus. mBio 10(2). pii: e00215-19. https://doi.org/10.1128/mbio.00215-19
Martinez J, Malireddi RK, Lu Q, Cunha LD, Pelletier S, Gingras S, Orchard R, Guan JL, Tan H, Peng J, Kanneganti TD, Virgin HW, Green DR (2015) Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat Cell Biol 17(7):893–906
Perez-Cuesta U, Aparicio-Fernandez L, Guruceaga X, Martin-Souto L, Abad-Diaz-de-Cerio A, Antoran A, Buldain I, Hernando FL, Ramirez-Garcia A, Rementeria A (2019) Melanin and pyomelanin in Aspergillus fumigatus: from its genetics to host interaction. Int Microbiol
Pihet M, Vandeputte P, Tronchin G, Renier G, Saulnier P, Georgeault S, Mallet R, Chabasse D, Symoens F, Bouchara JP (2009) Melanin is an essential component for the integrity of the cell wall of Aspergillus fumigatus conidia. BMC Microbiol 24(9):177
Pinto L, Granja LFZ, Almeida MA, Alviano DS, Silva MHD, Ejzemberg R, Rozental S, Alviano CS (2018) Melanin particles isolated from the fungus Fonsecaea pedrosoiactivates the human complement system. Mem Inst Oswaldo Cruz 113(8):e180120
Rambach G, Blum G, Latgé JP, Fontaine T, Heinekamp T, Hagleitner M, Jeckström H, Weigel G, Würtinger P, Pfaller K, Krappmann S, Löffler J, Lass-Flörl C, Speth C (2015) Identification of Aspergillus fumigatus surface components that mediate interaction of conidia and hyphae with human platelets. J Infect Dis 212(7):1140–1149
Riley PA (1997) Molecules in focus: melanin. Int J Biochem Cell Biol 29:1235–1239
Rosas AL, MacGill RS, Nosanchuk JD, Kozel TR, Casadevall A (2002) Activation of the alternative complement pathway by fungal melanins. Clin Diagn Lab Immunol 9(1):144–148
Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, Komatsu M, Tanaka K, Cleveland JL, Withoff S, Green DR (2007) Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450(7173):1253–1257
Schmidt H, Vlaic S, Krüger T, Schmidt F, Balkenhol J, Dandekar T, Guthke R, Kniemeyer O, Heinekamp T, Brakhage AA (2018) Proteomics of Aspergillus fumigatus conidia-containing phagolysosomes identifies processes governing immune evasion. Mol Cell Proteomics 17(6):1084–1096
Smith DFQ, Casadevall A (2019) The role of melanin in fungal pathogenesis for animal hosts. Curr Top Microbiol Immunol 422:1–30
Solano F (2014) Melanins: skin pigments and much more—types, structural models, biological functions, and formation routes. New J Sci 1–28
Stappers MHT, Clark AE, Aimanianda V, Bidula S, Reid DM, Asamaphan P, Hardison SE, Dambuza IM, Valsecchi I, Kerscher B, Plato A, Wallace CA, Yuecel R, Hebecker B, da Glória Teixeira Sousa M, Cunha C, Liu Y, Feizi T, Brakhage AA, Kwon-Chung KJ, Gow NAR, Zanda M, Piras M, Zanato C, Jaeger M, Netea MG, van de Veerdonk FL, Lacerda JF, Campos A, Carvalho A, Willment JA, Latgé JP, Brown GD (2018) Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus. Nature 555(7696):382–386
Sugareva V, Härtl A, Brock M, Hübner K, Rohde M, Heinekamp T, Brakhage AA (2006) Characterisation of the laccase-encoding gene abr2 of the dihydroxynaphthalene-like melanin gene cluster of Aspergillus fumigatus. ArchMicrobiol 186(5):345–355
Tsai HF, Chang YC, Washburn RG, Wheeler MH, Kwon-Chung KJ (1998) The developmentally regulated alb1 gene of Aspergillus fumigatus: its role in modulation of conidial morphology and virulence. J Bacteriol 180(12):3031–3038
Tsai HF, Wheeler MH, Chang YC, Kwon-Chung KJ (1999) A developmentally regulated gene cluster involved in conidial pigment biosynthesis in Aspergillus fumigatus. J Bacteriol 181(20):6469–6477
Thywißen A, Heinekamp T, Dahse HM, Schmaler-Ripcke J, Nietzsche S, Zipfel PF, Brakhage AA (2011) Conidial dihydroxynaphthalene melanin of the human pathogenic fungus Aspergillus fumigatus interferes with the host endocytosis pathway. Front Microbiol 3(2):96
Upadhyay S, Torres G, Lin X (2013) Laccases involved in 1,8-dihydroxynaphthalenemelanin biosynthesis in Aspergillus fumigatus are regulated by developmental factors and copper homeostasis. Eukaryot Cell 12(12):1641–1652
Upadhyay S, Xu X, Lin X (2016) Interactions between melanin enzymes and their a typical recruitment to the secretory pathway by palmitoylation. mBio. 7(6). pii: e01925-16. https://doi.org/10.1128/mbio
Upadhyay S, Xu X, Lowry D, Jackson JC, Roberson RW, Lin X (2016b) Subcellular Compartmentalization and trafficking of the biosynthetic machinery for fungal melanin. Cell Rep 14(11):2511–2518
Volling K, Thywissen A, Brakhage AA, Saluz HP (2011) Phagocytosis of melanized Aspergillus conidia by macrophages exerts cytoprotective effects by sustained PI3K/Akt signalling. Cell Microbiol 13(8):1130–1148
Wong SSW, Rani M, Dodagatta-Marri E, Ibrahim-Granet O, Kishore U, Bayry J, Latgé JP, Sahu A, Madan T, Aimanianda V (2018) Fungal melanin stimulates surfactant protein D-mediated opsonization of and host immune response to Aspergillus fumigatus spores. J Biol Chem 293(13):4901–4912
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Chamilos, G., Carvalho, A. (2020). Aspergillus fumigatus DHN-Melanin. In: Latgé, JP. (eds) The Fungal Cell Wall . Current Topics in Microbiology and Immunology, vol 425. Springer, Cham. https://doi.org/10.1007/82_2020_205
Download citation
DOI: https://doi.org/10.1007/82_2020_205
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-49927-3
Online ISBN: 978-3-030-49928-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)