Aspergillus fumigatus melanins: interference with the host endocytosis pathway and impact on virulence
Open accessAbstract
The opportunistic human pathogenic fungus Aspergillus fumigatus produces at least two types of melanin, namely pyomelanin and dihydroxynaphthalene (DHN) melanin. Pyomelanin is produced during tyrosine catabolism via accumulation of homogentisic acid. Although pyomelanin protects the fungus against reactive oxygen species (ROS) and acts as a defense compound in response to cell wall stress, mutants deficient for pyomelanin biosynthesis do not differ in virulence when tested in a murine infection model for invasive pulmonary aspergillosis. DHN melanin is responsible for the characteristic gray-greenish color of A. fumigatus conidia. Mutants lacking a functional polyketide synthase PksP, the enzyme responsible for the initial step in DHN-melanin formation, i.e., the synthesis of naphthopyrone, produce white spores and are attenuated in virulence. The activity of PksP was found to be essential not only for inhibition of apoptosis of phagocytes by interfering with the host PI3K/Akt signaling cascade but also for effective inhibition of acidification of conidia-containing phagolysosomes. These features allow A. fumigatus to survive in phagocytes and thereby to escape from human immune effector cells and to become a successful pathogen.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In Aspergillus fumigatus, melanin in conidial walls is essential for the proper expression of adhesins and other virulence factors, while inducing only minimal inflammatory cytokine responses to circumvent host antifungal defenses.
“In A. fumigatus, melanin in conidial walls is essential for the proper expression of adhesins and other virulence factors, while inducing only minimal inflammatory cytokine responses to circumvent host antifungal defenses [40,41].”
From Fungal Melanin in Plant Pathogens: Complex Biosynthesis Pathways and Diverse Biological Functions (2025) · cites this paper as [41]
The ‘Interference of DHN melanin with immune cells’ section (page unavailable) says wild-type conidia and melanin ghosts weakly induce proinflammatory cytokines, whereas pigmentless conidia trigger a stronger response. It does not say that melanin is essential for the proper expression of adhesins or other virulence factors; it describes melanin’s roles in masking immunogenic structures and interfering with phagocytes. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
LaeA, a Regulator of Morphogenetic Fungal Virulence Factors
Bok, J. W., Balajee, S. A., Marr, K. A., Andes, D., Nielsen, K. F., Frisvad, J. C., & Keller, N. P. (2005) · Eukaryotic Cell · doi:10.1128/ec.4.9.1574-1582.2005 · Cited by 283 · see citing works
Characterization of the SKN7 ortholog of Aspergillus fumigatus
Lamarre, C., Ibrahim-Granet, O., Du, C., Calderone, R., & Latgé, J.-P. (2007) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2007.01.009 · Cited by 109 · see citing works
Hydrolytic Polyketide Shortening by Ayg1p, a Novel Enzyme Involved in Fungal Melanin Biosynthesis
Fujii, I., Yasuoka, Y., Tsai, H.-F., Chang, Y. C., Kwon-Chung, K. J., & Ebizuka, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406758200 · Cited by 105 · see citing works
Flagged first, then by citations
Research works printed but not linked: 42
- Aimanianda V. Bayry J. Bozza S. Kniemeyer O. Perruccio K. Elluru S. R. (2009). Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature 460, 1117– 1121 10.1038/nature08264 19713928 · DOI · Paper page
- Altschul S. F. Gish W. Miller W. Myers E. W. Lipman D. J. (1990). Basic local alignment search tool. J. Mol. Biol. 215, 403– 410 10.1016/S0022-2836(05)80360-2 2231712 · DOI · Paper page
- Behnsen J. Lessing F. Schindler S. Wartenberg D. Jacobsen I. D. Thoen M. (2010). Secreted Aspergillus fumigatus protease Alp1 degrades human complement proteins C3, C4, and C5. Infect. Immun. 78, 3585– 3594 10.1128/IAI.01353-09 20498262 PMC2916278 · DOI
- Brakhage A. A. (2005). Systemic fungal infections caused by Aspergillus species: epidemiology, infection process and virulence determinants. Curr. Drug Targets 6, 875– 886 10.2174/138945005774912717 16375671 · DOI
- Chai L. Y. Netea M. G. Sugui J. Vonk A. G. Van De Sande W. W. Warris A. (2010). Aspergillus fumigatus conidial melanin modulates host cytokine response. Immunobiology 215, 915– 920 10.1016/j.imbio.2009.10.002 19939494 PMC2891869 · DOI
- Doering T. L. Nosanchuk J. D. Roberts W. K. Casadevall A. (1999). Melanin as a potential cryptococcal defence against microbicidal proteins. Med. Mycol. 37, 175– 181 10421849
- Fallon J. P. Reeves E. P. Kavanagh K. (2010). Inhibition of neutrophil function following exposure to the Aspergillus fumigatus toxin fumagillin. J. Med. Microbiol. 59, 625– 633 10.1099/jmm.0.018192-0 20203215 · DOI
- Grosse C. Heinekamp T. Kniemeyer O. Gehrke A. Brakhage A. A. (2008). Protein kinase A regulates growth, sporulation, and pigment formation in Aspergillus fumigatus. Appl. Environ. Microbiol. 74, 4923– 4933 10.1128/AEM.00470-08 18539819 PMC2519360 · DOI
- Hartmann T. Cairns T. C. Olbermann P. Morschhauser J. Bignell E. M. Krappmann S. (2011). Oligopeptide transport and regulation of extracellular proteolysis are required for growth of Aspergillus fumigatus on complex substrates but not for virulence. Mol. Microbiol. 82, 917– 935 10.1111/j.1365-2958.2011.07868.x 22023286 · DOI
- Jacobson E. S. (2000). Pathogenic roles for fungal melanins. Clin. Microbiol. Rev. 13, 708– 717 10.1128/CMR.13.4.708-717.2000 11023965 PMC88958 · DOI · Paper page
- Jahn B. Boukhallouk F. Lotz J. Langfelder K. Wanner G. Brakhage A. A. (2000). Interaction of human phagocytes with pigmentless Aspergillus conidia. Infect. Immun. 68, 3736– 3739 10.1128/IAI.68.6.3736-3739.2000 10816538 PMC97669 · DOI
- Jahn B. Koch A. Schmidt A. Wanner G. Gehringer H. Bhakdi S. (1997). Isolation and characterization of a pigmentless-conidium mutant of Aspergillus fumigatus with altered conidial surface and reduced virulence. Infect. Immun. 65, 5110– 5117 9393803 PMC175736
- Jahn B. Langfelder K. Schneider U. Schindel C. Brakhage A. A. (2002). PKSP-dependent reduction of phagolysosome fusion and intracellular kill of Aspergillus fumigatus conidia by human monocyte-derived macrophages. Cell. Microbiol. 4, 793– 803 10.1046/j.1462-5822.2002.00228.x 12464010 · DOI
- Jain R. Valiante V. Remme N. Docimo T. Heinekamp T. Hertweck C. (2011). The MAP kinase MpkA controls cell wall integrity, oxidative stress response, gliotoxin production and iron adaptation in Aspergillus fumigatus. Mol. Microbiol. 82, 39– 53 10.1111/j.1365-2958.2011.07778.x 21883519 PMC3229709 · DOI · Paper page
- Keller S. Macheleidt J. Scherlach K. Schmaler-Ripcke J. Jacobsen I. D. Heinekamp T. (2011). Pyomelanin formation in Aspergillus fumigatus requires HmgX and the transcriptional activator HmgR but is dispensable for virulence. PLoS ONE 6: e26604 10.1371/journal.pone.0026604 22046314 PMC3203155 · DOI
- Langfelder K. Jahn B. Gehringer H. Schmidt A. Wanner G. Brakhage A. A. (1998). Identification of a polyketide synthase gene (pksP) of Aspergillus fumigatus involved in conidial pigment biosynthesis and virulence. Med. Microbiol. Immunol. (Berl.) 187, 79– 89 9832321
- Langfelder K. Philippe B. Jahn B. Latge J. P. Brakhage A. A. (2001). Differential expression of the Aspergillus fumigatus pksP gene detected in vitro and in vivo with green fluorescent protein. Infect. Immun. 69, 6411– 6418 10.1128/IAI.69.10.6411-6418.2001 11553585 PMC98776 · DOI
- Langfelder K. Streibel M. Jahn B. Haase G. Brakhage A. A. (2003). Biosynthesis of fungal melanins and their importance for human pathogenic fungi. Fungal Genet. Biol. 38, 143– 158 10.1016/S1087-1845(02)00526-1 12620252 · DOI · Paper page
- Lessing F. Kniemeyer O. Wozniok I. Loeffler J. Kurzai O. Haertl A. (2007). The Aspergillus fumigatus transcriptional regulator AfYap1 represents the major regulator for defense against reactive oxygen intermediates but Is dispensable for pathogenicity in an intranasal mouse infection model. Eukaryot. Cell. 6, 2290– 2302 10.1128/EC.00267-07 17921349 PMC2168236 · DOI · Paper page
- Liebmann B. Gattung S. Jahn B. Brakhage A. A. (2003). cAMP signaling in Aspergillus fumigatus is involved in the regulation of the virulence gene pksP and in defense against killing by macrophages. Mol. Genet. Genomics 269, 420– 435 10.1007/s00438-003-0852-0 12734751 · DOI
- Liebmann B. Muller M. Braun A. Brakhage A. A. (2004). The cyclic AMP-dependent protein kinase a network regulates development and virulence in Aspergillus fumigatus. Infect. Immun. 72, 5193– 5203 10.1128/IAI.72.9.5193-5203.2004 15322014 PMC517480 · DOI
- McDonagh A. Fedorova N. D. Crabtree J. Yu Y. Kim S. Chen D. (2008). Sub-telomere directed gene expression during initiation of invasive aspergillosis. PLoS Pathog. 4: e1000154 10.1371/journal.ppat.1000154 18787699 PMC2526178 · DOI
- Mitchell C. G. Slight J. Donaldson K. (1997). Diffusible component from the spore surface of the fungus Aspergillus fumigatus which inhibits the macrophage oxidative burst is distinct from gliotoxin and other hyphal toxins. Thorax 52, 796– 801 9371210 PMC1758635
- Morton C. O. Varga J. J. Hornbach A. Mezger M. Sennefelder H. Kneitz S. (2011). The temporal dynamics of differential gene expression in Aspergillus fumigatus interacting with human immature dendritic cells in vitro. PLoS ONE 6: e16016 10.1371/journal.pone.0016016 21264256 PMC3021540 · DOI
- Nosanchuk J. D. Casadevall A. (2006). Impact of melanin on microbial virulence and clinical resistance to antimicrobial compounds. Antimicrob. Agents Chemother. 50, 3519– 3528 10.1128/AAC.00545-06 17065617 PMC1635213 · DOI
- Palmer J. M. Keller N. P. (2010). Secondary metabolism in fungi: does chromosomal location matter? Curr. Opin. Microbiol. 13, 431– 436 10.1016/j.mib.2010.04.008 20627806 PMC2922032 · DOI
- Pihet M. Vandeputte P. Tronchin G. Renier G. Saulnier P. Georgeault S. (2009). Melanin is an essential component for the integrity of the cell wall of Aspergillus fumigatus conidia. sBMC Microbiol. 9: 177 10.1186/1471-2180-9-177 19703288 PMC2740851 · DOI · Paper page
- Riley P. A. (1997). Melanin. Int. J. Biochem. Cell Biol. 29, 1235– 1239 10.1016/S1357-2725(97)00013-7 9451820 · DOI
- Scharf D. H. Heinekamp T. Remme N. Hortschansky P. Brakhage A. A. Hertweck C. (2012). Biosynthesis and function of gliotoxin in Aspergillus fumigatus. Appl. Microbiol. Biotechnol. 93, 467– 472 10.1007/s00253-011-3689-1 22094977 · DOI
- Schmaler-Ripcke J. Sugareva V. Gebhardt P. Winkler R. Kniemeyer O. Heinekamp T. (2009). Production of pyomelanin, a second type of melanin, via the tyrosine degradation pathway in Aspergillus fumigatus. Appl. Environ. Microbiol. 75, 493– 503 10.1128/AEM.02077-08 19028908 PMC2620705 · DOI
- Slesiona S. Gressler M. Mihlan M. Zaehle C. Schaller M. Barz D. (2012). Persistence versus escape: Aspergillus terreus and Aspergillus fumigatus employ different strategies during interactions with macrophages. PLoS ONE 7: e31223 10.1371/journal.pone.0031223 22319619 PMC3272006 · DOI
- Sugareva V. Hartl A. Brock M. Hubner K. Rohde M. Heinekamp T. (2006). Characterisation of the laccase-encoding gene abr2 of the dihydroxynaphthalene-like melanin gene cluster of Aspergillus fumigatus. Arch. Microbiol. 186, 345– 355 10.1007/s00203-006-0144-2 16988817 · DOI
- Sugui J. A. Pardo J. Chang Y. C. Mullbacher A. Zarember K. A. Galvez E. M. (2007). Role of laeA in the regulation of alb1, gliP, conidial morphology, and virulence in Aspergillus fumigatus. Eukaryot. Cell 6, 1552– 1561 10.1128/EC.00140-07 17630330 PMC2043373 · DOI
- Thywißen A. Heinekamp T. Dahse H.-M. Schmaler-Ripcke J. Nietsche S. Zipfel P. F. (2011). Conidial dihydroxynaphthalene melanin of the human pathogenic fungus Aspergillus fumigatus interferes with the host endocytosis pathway. Front. Microbio. 2: 96 10.3389/fmicb.2011.00096 21747802 PMC3128974 · DOI
- Tsai H. F. Chang Y. C. Washburn R. G. Wheeler M. H. Kwon-Chung K. J. (1998). The developmentally regulated alb1 gene of Aspergillus fumigatus: its role in modulation of conidial morphology and virulence. J. Bacteriol. 180, 3031– 3038 9620950 PMC107801
- Tsai H. F. Fujii I. Watanabe A. Wheeler M. H. Chang Y. C. Yasuoka Y. (2001). Pentaketide melanin biosynthesis in Aspergillus fumigatus requires chain-length shortening of a heptaketide precursor. J. Biol. Chem. 276, 29292– 29298 10.1074/jbc.M101998200 11350964 · DOI · Paper page
- Tsai H. F. Wheeler M. H. Chang Y. C. Kwon-Chung K. J. (1999). A developmentally regulated gene cluster involved in conidial pigment biosynthesis in Aspergillus fumigatus. J. Bacteriol. 181, 6469– 6477 10515939 PMC103784
- Valiante V. Jain R. Heinekamp T. Brakhage A. A. (2009). The MpkA MAP kinase module regulates cell wall integrity signaling and pyomelanin formation in Aspergillus fumigatus. Fungal Genet. Biol. 46, 909– 918 10.1016/j.fgb.2009.08.005 19715768 · DOI
- Volling K. Thywissen A. Brakhage A. A. Saluz H. P. (2011). Phagocytosis of melanized Aspergillus conidia by macrophages exerts cytoprotective effects by sustained PI3K/Akt signalling. Cell. Microbiol. 13, 1130– 1148 10.1111/j.1462-5822.2011.01605.x 21501368 · DOI
- Wartenberg D. Lapp K. Jacobsen I. D. Dahse H. M. Kniemeyer O. Heinekamp T. (2011). Secretome analysis of Aspergillus fumigatus reveals Asp-hemolysin as a major secreted protein. Int. J. Med. Microbiol. 301, 602– 611 10.1016/j.ijmm.2011.04.016 21658997 · DOI
- Wheeler M. H. Bell A. A. (1988). Melanins and their importance in pathogenic fungi. Curr. Top. Med. Mycol. 2, 338– 387 3288360
- Zhao W. Panepinto J. C. Fortwendel J. R. Fox L. Oliver B. G. Askew D. S. (2006). Deletion of the regulatory subunit of protein kinase A in Aspergillus fumigatus alters morphology, sensitivity to oxidative damage, and virulence. Infect. Immun. 74, 4865– 4874 10.1128/IAI.00565-06 16861675 PMC1539607 · DOI
Cited by
Sorted by citations
Molecular architecture of fungal cell walls revealed by solid-state NMR
Kang, X., Kirui, A., Muszyński, A., Widanage, M. C. D., Chen, A., Azadi, P., Wang, P., Mentink-Vigier, F., & Wang, T. (2018) · Nature Communications · doi:10.1038/s41467-018-05199-0 · Cited by 356 · see citing works
Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus
Stappers, M. H. T., Clark, A. E., Aimanianda, V., Bidula, S., Reid, D. M., Asamaphan, P., Hardison, S. E., Dambuza, I. M., Valsecchi, I., Kerscher, B., et al. (2018) · Nature · doi:10.1038/nature25974 · Cited by 200 · see citing works
Self-citationLatgé, J.-P., Beauvais, A., & Chamilos, G. (2017) · Annual Review of Microbiology · doi:10.1146/annurev-micro-030117-020406 · Cited by 207 · see citing works
Functional duality of the cell wall
Latgé, J.-P., & Beauvais, A. (2014) · Current Opinion in Microbiology · doi:10.1016/j.mib.2014.05.009 · Cited by 144 · see citing works
Interactions of Aspergillus fumigatus Conidia with Airway Epithelial Cells: A Critical Review
Croft, C. A., Culibrk, L., Moore, M. M., & Tebbutt, S. J. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.00472 · Cited by 142 · see citing works
Bayry, J., Beaussart, A., Dufrêne, Y. F., Sharma, M., Bansal, K., Kniemeyer, O., Aimanianda, V., Brakhage, A. A., Kaveri, S. V., Kwon-Chung, K. J., et al. (2014) · Infection and Immunity · doi:10.1128/iai.01726-14 · Cited by 137 · see citing works
Self-citationBiofilm formation by<b><i>Aspergillus fumigatus</i></b>
Kaur, S., & Singh, S. (2013) · Medical Mycology · doi:10.3109/13693786.2013.819592 · Cited by 128 · see citing works
Interference of Aspergillus fumigatus with the immune response
Heinekamp, T., Schmidt, H., Lapp, K., Pähtz, V., Shopova, I., Köster-Eiserfunke, N., Krüger, T., Kniemeyer, O., & Brakhage, A. A. (2015) · Seminars in Immunopathology · doi:10.1007/s00281-014-0465-1 · Cited by 123 · see citing works
Self-citationVoltersen, V., Blango, M. G., Herrmann, S., Schmidt, F., Heinekamp, T., Strassburger, M., Krüger, T., Bacher, P., Lother, J., Weiss, E., et al. (2018) · mBio · doi:10.1128/mbio.01557-18 · Cited by 71 · see citing works
Self-citationWiemann, P., Lechner, B. E., Baccile, J. A., Velk, T. A., Yin, W.-B., Bok, J. W., Pakala, S., Losada, L., Nierman, W. C., Schroeder, F. C., et al. (2014) · Frontiers in Microbiology · doi:10.3389/fmicb.2014.00530 · Cited by 60 · see citing works
Rambach, G., Blum, G., Latgé, J.-P., Fontaine, T., Heinekamp, T., Hagleitner, M., Jeckström, H., Weigel, G., Würtinger, P., Pfaller, K., et al. (2015) · Journal of Infectious Diseases · doi:10.1093/infdis/jiv191 · Cited by 57 · see citing works
Self-citationEscobar, N., Ordonez, S. R., Wösten, H. A. B., Haas, P.-J. A., de Cock, H., & Haagsman, H. P. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.00438 · Cited by 48 · see citing works
Guruceaga, X., Ezpeleta, G., Mayayo, E., Sueiro-Olivares, M., Abad-Diaz-De-Cerio, A., Aguirre Urízar, J. M., Liu, H. G., Wiemann, P., Bok, J. W., Filler, S. G., et al. (2018) · Virulence · doi:10.1080/21505594.2018.1526528 · Cited by 44 · see citing works
Bellanger, A.-P., Tatara, A. M., Shirazi, F., Gebremariam, T., Albert, N. D., Lewis, R. E., Ibrahim, A. S., & Kontoyiannis, D. P. (2016) · Journal of Infectious Diseases · doi:10.1093/infdis/jiw090 · Cited by 41 · see citing works
Fungal Melanin in Plant Pathogens: Complex Biosynthesis Pathways and Diverse Biological Functions
Jia, H., Liu, N., Zhang, L., Li, P., Meng, Y., Yuan, W., Li, H., Tantai, D., Qu, Q., Cao, Z., et al. (2025) · Plants · doi:10.3390/plants14142121 · Cited by 18 · see citing works
- Authors
- Heinekamp, T., Thywißen, A., Macheleidt, J., Keller, S., Valiante, V., & Brakhage, A. A.
- Affiliations
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
- Corresponding author
- Heinekamp, Thorsten
- Venue
- Frontiers in Microbiology
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 3
- Pages
- 440-440
- ISSN
- 1664-302X (ISSN-L)
- PMC
- PMC3548413
- OpenAlex
- W2078893340
- Cited by
- 216
- References
- 3
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 13 · 2023: 17 · 2022: 13 · 2021: 25 · 2020: 16 · 2019: 15 · 2018: 20 · 2017: 20 · 2016: 24 · 2015: 8 · 2014: 17 · 2013: 10
- FWCI
- 7.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Microbiology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- International Leibniz Research School for Microbial and Biomolecular Interactions
- Leibniz-Gemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Aspergillus fumigatus, fungal melanin, pyomelanin, endocytosis, virulence, naphthopyrones, PI3K/Akt signaling, invasive pulmonary aspergillosis, homogentisic acid, tyrosine catabolism, reactive oxygen species defense, conidia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
