Abstract
Aspergillus fumigatus is a ubiquitous fungal pathogen associated with several life-threatening infections in patients suffering from chronic lung inflammatory diseases and immune deficiencies. Multiple factors contribute towards the survival and adaptation of A. fumigatus in the host and determine its pathogenicity. A limited spectrum of antifungal drugs is available for treating A. fumigatus infections which mainly target either cell wall or cell membrane biosynthesis. The clinical usage of these drugs is becoming progressively restricted due of the emergence of resistant A. fumigatus strains. Thus, there is an urgent unmet need to analyse other virulence determinants of A. fumigatus, in addition to screening suitable and effective targets for the prospective antifungal drugs. The present review elaborates A. fumigatus virulence determinants associated with cell surface organisation such as hydrophobins (rodlet layer formation), chitin, glucans and galactosaminogalactan. Besides, secondary metabolites such as gliotoxin, melanin and siderophores (iron homeostasis mechanism) have also been discussed. The exhaustive understanding of these virulence determinants could potentially lead to the discovery of novel targets that could be exploited to either discover new molecules or enhance the efficacy of known antifungal drugs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Not applicable.
References
Abad A, Fernández-Molina JV, Bikandi J et al (2010) What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis. Rev Iberoam Micol 27:155–182. https://doi.org/10.1016/j.riam.2010.10.003
Aimanianda V, Bayry J, Bozza S et al (2009) Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature 460:1117–1121. https://doi.org/10.1038/nature08264
Akoumianaki T, Kyrmizi I, Valsecchi I et al (2016) Aspergillus cell wall melanin blocks LC3-associated phagocytosis to promote pathogenicity. Cell Host Microbe 19:79–90. https://doi.org/10.1016/j.chom.2015.12.002
Allam NG, El-Zaher EA (2012) Protective role of Aspergillus fumigatus melanin against ultraviolet (UV) irradiation and Bjerkandera adusta melanin as a candidate vaccine against systemic candidiasis. Afr J Biotech 11:6566–6577. https://doi.org/10.4314/ajb.v11i24
Altwasser R, Baldin C, Weber J et al (2015) Network modeling reveals cross talk of MAP kinases during adaptation to caspofungin stress in Aspergillus fumigatus. PLoS ONE 10:1–21. https://doi.org/10.1371/journal.pone.0136932
Aruanno M, Glampedakis E, Lamoth F (2019) Echinocandins for the treatment of invasive aspergillosis: from laboratory to bedside. Antimicrob Agents Chemother 63:1–13. https://doi.org/10.1128/AAC.00399-19
Balajee SA, Baddley JW, Peterson SW et al (2009) Aspergillus alabamensis, a new clinically relevant species in the section Terrei. Eukaryot Cell 8:713–722. https://doi.org/10.1128/EC.00272-08
Bayry J, Aimanianda V, Guijarro JI et al (2012) Hydrophobins- unique fungal proteins. PLOS Pathog 8:e1002700. https://doi.org/10.1371/journal.ppat.1002700
Bayry J, Beaussart A, Dufrêne YF et al (2014) Surface structure characterization of Aspergillus fumigatus conidia mutated in the melanin synthesis pathway and their human cellular immune response. Infect Immun 82:3141–3153. https://doi.org/10.1128/IAI.01726-14
Beauvais A, Latgé J-P (2015) Aspergillus biofilm in vitro and in vivo. Microbiol Spectr 3:1–10. https://doi.org/10.1128/microbiolspec.MB-0017-2015
Beauvais A, Maubon D, Park S et al (2005) Two alpha(1–3) glucan synthases with different functions in Aspergillus fumigatus. Appl Environ Microbiol 71:1531–1538. https://doi.org/10.1128/AEM.71.3.1531-1538.2005
Beauvais A, Schmidt C, Guadagnini S et al (2007) An extracellular matrix glues together the aerial-grown hyphae of Aspergillus fumigatus. Cell Microbiol 9:1588–1600. https://doi.org/10.1111/j.1462-5822.2007.00895.x
Beauvais A, Bozza S, Kniemeyer O et al (2013) Deletion of the α-(1,3)-glucan synthase genes induces a restructuring of the conidial cell wall responsible for the avirulence of Aspergillus fumigatus. PLoS Pathog 9:e1003716. https://doi.org/10.1371/journal.ppat.1003716
Beauvais A, Fontaine T, Aimanianda V, Latgé J-P (2014) Aspergillus cell wall and biofilm. Mycopathologia 178:371–377. https://doi.org/10.1007/s11046-014-9766-0
Bhetariya PJ, Madan T, Basir SF et al (2011) Allergens/Antigens, toxins and polyketides of important Aspergillus species. Indian J Clin Biochem 26:104–119. https://doi.org/10.1007/s12291-011-0131-5
Bok JW, Chung D, Balajee SA et al (2006) GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus virulence. Infect Immun 74:6761–6768. https://doi.org/10.1128/IAI.00780-06
Braga GUL, Rangel DEN, Fernandes ÉKK et al (2015) Molecular and physiological effects of environmental UV radiation on fungal conidia. Curr Genet 61:405–425. https://doi.org/10.1007/s00294-015-0483-0
Brakhage AA, Liebmann B (2005) Aspergillus fumigatus conidial pigment and cAMP signal transduction: significance for virulence. Med Mycol 43(Suppl 1):S75-82. https://doi.org/10.1080/13693780400028967
Brandon M, Howard B, Lawrence C, Laubenbacher R (2015) Iron acquisition and oxidative stress response in Aspergillus fumigatus. BMC Syst Biol 9:19. https://doi.org/10.1186/s12918-015-0163-1
Briard B, Muszkieta L, Latgé J-P, Fontaine T (2016) Galactosaminogalactan of Aspergillus fumigatus, a bioactive fungal polymer. Mycologia 108:572–580. https://doi.org/10.3852/15-312
Bruder Nascimento de O ACM, Dos Reis TF, de Castro PA et al (2016) Mitogen activated protein kinases SakA(HOG1) and MpkC collaborate for Aspergillus fumigatus virulence. Mol Microbiol 100:841–859. https://doi.org/10.1111/mmi.13354
Campoy S, Adrio JL (2017) Antifungals. Biochem Pharmacol 133:86–96. https://doi.org/10.1016/j.bcp.2016.11.019
Cerqueira GC, Arnaud MB, Inglis DO et al (2014) The Aspergillus Genome Database: multispecies curation and incorporation of RNA-Seq data to improve structural gene annotations. Nucleic Acids Res 42:D705-710. https://doi.org/10.1093/nar/gkt1029
Chai CL, Waring P (2000) Redox sensitive epidithiodioxopiperazines in biological mechanisms of toxicity. Redox Rep 5:257–264. https://doi.org/10.1179/135100000101535799
Chotirmall SH, Mirkovic B, Lavelle GM, McElvaney NG (2014) Immunoevasive Aspergillus virulence factors. Mycopathologia 178:363–370. https://doi.org/10.1007/s11046-014-9768-y
Colley T, Sehra G, Daly L et al (2019) Antifungal synergy of a topical triazole, PC945, with a systemic triazole against respiratory Aspergillus fumigatus infection. Sci Rep 9:9482. https://doi.org/10.1038/s41598-019-45890-w
Cramer RA, Gamcsik MP, Brooking RM et al (2006) Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production. Eukaryot Cell 5:972–980. https://doi.org/10.1128/EC.00049-06
Cramer RA, Stajich JE, Yamanaka Y et al (2006) Phylogenomic analysis of non-ribosomal peptide synthetases in the genus Aspergillus. Gene 383:24–32. https://doi.org/10.1016/j.gene.2006.07.008
Croft CA, Culibrk L, Moore MM, Tebbutt SJ (2016) Interactions of Aspergillus fumigatus conidia with airway epithelial cells: a critical review. Front Microbiol 7:1–15. https://doi.org/10.3389/fmicb.2016.00472
Da Silva CA, Chalouni C, Williams A et al (2009) Chitin is a size-dependent regulator of macrophage TNF and IL-10 production. J Immunol 182:3573–3582. https://doi.org/10.4049/jimmunol.0802113
Dagenais TRT, Keller NP (2009) Pathogenesis of Aspergillus fumigatus in invasive aspergillosis. Clin Microbiol Rev 22:447–465. https://doi.org/10.1128/CMR.00055-08
Denning DW, Pleuvry A, Cole DC (2011) Global burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis. Bull World Health Organ 89:864–872. https://doi.org/10.2471/BLT.11.089441
Denning DW, Pleuvry A, Cole DC (2013) Global burden of allergic bronchopulmonary aspergillosis with asthma and its complication chronic pulmonary aspergillosis in adults. Med Mycol 51:361–370. https://doi.org/10.3109/13693786.2012.738312
Dichtl K, Samantaray S, Aimanianda V et al (2015) Aspergillus fumigatus devoid of cell wall β-1,3-glucan is viable, massively sheds galactomannan and is killed by septum formation inhibitors. Mol Microbiol 95:458–471. https://doi.org/10.1111/mmi.12877
Dolan SK, Owens RA, O’Keeffe G et al (2014) Regulation of nonribosomal peptide synthesis: bis-thiomethylation attenuates gliotoxin biosynthesis in Aspergillus fumigatus. Chem Biol 21:999–1012. https://doi.org/10.1016/j.chembiol.2014.07.006
Eisenman HC, Casadevall A (2012) Synthesis and assembly of fungal melanin. Appl Microbiol Biotechnol 93:931–940. https://doi.org/10.1007/s00253-011-3777-2
Ferling I, Dunn JD, Ferling A et al (2020) Conidial melanin of the human-pathogenic fungus Aspergillus fumigatus disrupts cell autonomous defenses in Amoebae. mBio 11:e00862-20. https://doi.org/10.1128/mBio.00862-20
Fontaine T, Beauvais A, Loussert C et al (2010) Cell wall alpha1-3glucans induce the aggregation of germinating conidia of Aspergillus fumigatus. Fungal Genet Biol 47:707–712. https://doi.org/10.1016/j.fgb.2010.04.006
Fontaine T, Delangle A, Simenel C et al (2011) Galactosaminogalactan, new immunosuppressive polysaccharide of Aspergillus fumigatus. PLoS Pathog 7:e1002372. https://doi.org/10.1371/journal.ppat.1002372
Ganz T (2009) Iron in innate immunity: starve the invaders. Curr Opin Immunol 21:63–67. https://doi.org/10.1016/j.coi.2009.01.011
Gardiner DM, Howlett BJ (2005) Bioinformatic and expression analysis of the putative gliotoxin biosynthetic gene cluster of Aspergillus fumigatus. FEMS Microbiol Lett 248:241–248. https://doi.org/10.1016/j.femsle.2005.05.046
Gardiner DM, Cozijnsen AJ, Wilson LM et al (2004) The sirodesmin biosynthetic gene cluster of the plant pathogenic fungus Leptosphaeria maculans. Mol Microbiol 53:1307–1318. https://doi.org/10.1111/j.1365-2958.2004.04215.x
Gardiner DM, Waring P, Howlett BJ (2005) The epipolythiodioxopiperazine (ETP) class of fungal toxins: distribution, mode of action, functions and biosynthesis. Microbiology 151:1021–1032. https://doi.org/10.1099/mic.0.27847-0
Gastebois A, Clavaud C, Aimanianda V, Latgé J-P (2009) Aspergillus fumigatus: cell wall polysaccharides, their biosynthesis and organization. Future Microbiol 4:583–595. https://doi.org/10.2217/fmb.09.29
Ghazaei C (2017) Molecular insights into pathogenesis and infection with Aspergillus fumigatus. Malays J Med Sci 24:10–20. https://doi.org/10.21315/mjms2017.24.1.2
Girois SB, Chapuis F, Decullier E, Revol BGP (2006) Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis. Eur J Clin Microbiol Infect Dis 25:138–149. https://doi.org/10.1007/s10096-005-0080-0
Gonçalves SS, Souza ACR, Chowdhary A et al (2016) Epidemiology and molecular mechanisms of antifungal resistance in Candida and Aspergillus. Mycoses 59:198–219. https://doi.org/10.1111/myc.12469
Gow NAR, Latge J-P, Munro CA (2017) The fungal cell wall: structure, biosynthesis, and function. Microbiol Spectr 5:1–25. https://doi.org/10.1128/microbiolspec.FUNK-0035-2016
Graf K, Khani SM, Ott E et al (2011) Five-years surveillance of invasive aspergillosis in a university hospital. BMC Infect Dis 11:163. https://doi.org/10.1186/1471-2334-11-163
Gravelat FN, Beauvais A, Liu H et al (2013) Aspergillus galactosaminogalactan mediates adherence to host constituents and conceals hyphal β-glucan from the immune system. PLoS Pathog 9:e1003575. https://doi.org/10.1371/journal.ppat.1003575
Gresnigt MS, Bozza S, Becker KL et al (2014) A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of Interleukin-1 receptor antagonist. PLoS Pathog 10:e1003936. https://doi.org/10.1371/journal.ppat.1003936
Groll AH, Rijnders BJA, Walsh TJ et al (2019) Clinical pharmacokinetics, pharmacodynamics, safety and efficacy of liposomal amphotericin b. Clin Infect Dis 68:S260–S274. https://doi.org/10.1093/cid/ciz076
Haas H, Eisendle M, Turgeon BG (2008) Siderophores in fungal physiology and virulence. Annu Rev Phytopathol 46:149–187. https://doi.org/10.1146/annurev.phyto.45.062806.094338
Heinekamp T, Thywissen A, Macheleidt J et al (2013) Aspergillus fumigatus melanins: interference with the host endocytosis pathway and impact on virulence. Front Microbiol 3:1–7. https://doi.org/10.3389/fmicb.2012.00440
Hernández-Chávez MJ, Pérez-García LA, Niño-Vega GA, Mora-Montes HM (2017) Fungal strategies to evade the host immune recognition. J Fungi (Basel) 3:51. https://doi.org/10.3390/jof3040051
Hiemenz JW, Walsh TJ (1996) Lipid formulations of amphotericin B: recent progress and future directions. Clin Infect Dis 22(Suppl 2):S133-144. https://doi.org/10.1093/clinids/22.supplement_2.s133
Hissen AHT, Chow JMT, Pinto LJ, Moore MM (2004) Survival of Aspergillus fumigatus in serum involves removal of iron from transferrin: the role of siderophores. Infect Immun 72:1402–1408. https://doi.org/10.1128/iai.72.3.1402-1408.2004
Hissen AHT, Wan ANC, Warwas ML et al (2005) The Aspergillus fumigatus siderophore biosynthetic gene sida, encoding l-ornithine n5-oxygenase, is required for virulence. Infect Immun 73:5493–5503. https://doi.org/10.1128/IAI.73.9.5493-5503.2005
Hoda S, Agarwal H, Ahluwalia SK et al (2019) Antifungal resistance analysis of environmental isolates of Aspergillus in North India. J Pure Appl Microbiol 13:385–392. https://doi.org/10.22207/JPAM.13.1.42
Hohl TM, Feldmesser M (2007) Aspergillus fumigatus: principles of pathogenesis and host defense. Eukaryot Cell 6:1953–1963. https://doi.org/10.1128/EC.00274-07
Hosseini M, Shakerimoghaddam A, Ghazalibina M, Khaledi A (2020) Aspergillus coinfection among patients with pulmonary tuberculosis in Asia and Africa countries; a systematic review and meta-analysis of cross-sectional studies. Microb Pathog 141:104018. https://doi.org/10.1016/j.micpath.2020.104018
Iqbal N, Irfan M, Mushtaq A, Jabeen K (2020) Underlying conditions and clinical spectrum of chronic pulmonary aspergillosis (cpa): an experience from a tertiary care hospital in Karachi, Pakistan. J Fungi 6:41. https://doi.org/10.3390/jof6020041
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:e4224. https://doi.org/10.1371/journal.pone.0004224
Jain R, Valiante V, Remme N et al (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. https://doi.org/10.1111/j.1365-2958.2011.07778.x
Jiménez-Ortigosa C, Aimanianda V, Muszkieta L et al (2012) Chitin synthases with a myosin motor-like domain control the resistance of Aspergillus fumigatus to echinocandins. Antimicrob Agents Chemother 56:6121–6131. https://doi.org/10.1128/AAC.00752-12
Kathiravan MK, Salake AB, Chothe AS et al (2012) The biology and chemistry of antifungal agents: a review. Bioorg Med Chem 20:5678–5698. https://doi.org/10.1016/j.bmc.2012.04.045
Kauffman CA (2006) Clinical efficacy of new antifungal agents. Curr Opin Microbiol 9:483–488. https://doi.org/10.1016/j.mib.2006.08.001
Keller NP, Turner G, Bennett JW (2005) Fungal secondary metabolism - from biochemistry to genomics. Nat Rev Microbiol 3:937–947. https://doi.org/10.1038/nrmicro1286
Kwon-Chung KJ, Sugui JA (2013) Aspergillus fumigatus-what makes the species a ubiquitous human fungal pathogen? PLoS Pathog 9:e1003743. https://doi.org/10.1371/journal.ppat.1003743
Kyrmizi I, Gresnigt MS, Akoumianaki T et al (2013) Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting Dectin-1/syk kinase signaling. J Immunol 191:1–16. https://doi.org/10.4049/jimmunol.1300132
Laniado-Laborín R, Cabrales-Vargas MN (2009) Amphotericin B: side effects and toxicity. Rev Iberoam Micol 26:223–227. https://doi.org/10.1016/j.riam.2009.06.003
Lass-Flörl C, Griff K, Mayr A et al (2005) Epidemiology and outcome of infections due to Aspergillus terreus: 10-year single centre experience. Br J Haematol 131:201–207. https://doi.org/10.1111/j.1365-2141.2005.05763.x
Latgé J-P, Beauvais A, Chamilos G (2017) The cell wall of the human fungal pathogen Aspergillus fumigatus: biosynthesis, organization, immune response, and virulence. Annu Rev Microbiol 71:99–116. https://doi.org/10.1146/annurev-micro-030117-020406
Lee MJ, Liu H, Barker BM et al (2015) The fungal exopolysaccharide galactosaminogalactan mediates virulence by enhancing resistance to neutrophil extracellular traps. PLoS Pathog 11:e1005187. https://doi.org/10.1371/journal.ppat.1005187
Lin C-J, Sasse C, Gerke J et al (2015) Transcription factor SomA is required for adhesion, development and virulence of the human pathogen Aspergillus fumigatus. PLoS Pathog 11:e1005205. https://doi.org/10.1371/journal.ppat.1005205
Loussert C, Schmitt C, Prevost MC et al (2010) In vivo biofilm composition of Aspergillus fumigatus. Cell Microbiol 12:405–410. https://doi.org/10.1111/j.1462-5822.2009.01409.x
Manfiolli AO, Siqueira FS, Dos Reis TF et al (2019) Mitogen-activated protein kinase cross-talk interaction modulates the production of melanins in Aspergillus fumigatus. mBio 10:1–17. https://doi.org/10.1128/mBio.00215-19
Maubon D, Park S, Tanguy M et al (2006) AGS3, an alpha(1–3)glucan synthase gene family member of Aspergillus fumigatus, modulates mycelium growth in the lung of experimentally infected mice. Fungal Genet Biol 43:366–375. https://doi.org/10.1016/j.fgb.2006.01.006
Morozov AA, Likhoshway YV (2016) Evolutionary history of the chitin synthases of eukaryotes. Glycobiology 26:635–639. https://doi.org/10.1093/glycob/cww018
Müller S, Baldin C, Groth M et al (2012) Comparison of transcriptome technologies in the pathogenic fungus Aspergillus fumigatus reveals novel insights into the genome and MpkA dependent gene expression. BMC Genomics 13:519. https://doi.org/10.1186/1471-2164-13-519
Muszkieta L, Aimanianda V, Mellado E et al (2014) Deciphering the role of the chitin synthase families 1 and 2 in the in vivo and in vitro growth of Aspergillus fumigatus by multiple gene targeting deletion. Cell Microbiol 16:1784–1805. https://doi.org/10.1111/cmi.12326
Nosanchuk JD, Casadevall A (2006) Impact of melanin on microbial virulence and clinical resistance to antimicrobial compounds. Antimicrob Agents Chemother 50:3519–3528. https://doi.org/10.1128/AAC.00545-06
Nosanchuk JD, Stark RE, Casadevall A (2015) Fungal melanin: what do we know about structure? Front Microbiol 6:1–7. https://doi.org/10.3389/fmicb.2015.01463
Odds FC, Brown AJP, Gow NAR (2003) Antifungal agents: mechanisms of action. Trends Microbiol 11:272–279. https://doi.org/10.1016/s0966-842x(03)00117-3
Ostrosky-Zeichner L (2004) Novel approaches to antifungal prophylaxis. Expert Opin Investig Drugs 13:665–672. https://doi.org/10.1517/13543784.13.6.665
Owens RA, O’Keeffe G, Smith EB et al (2015) Interplay between gliotoxin resistance, secretion, and the methyl/methionine cycle in Aspergillus fumigatus. Eukaryot Cell 14:941–957. https://doi.org/10.1128/EC.00055-15
Pardo J, Urban C, Galvez EM et al (2006) The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice. J Cell Biol 174:509–519. https://doi.org/10.1083/jcb.200604044
Paris S, Debeaupuis J-P, Crameri R et al (2003) Conidial hydrophobins of Aspergillus fumigatus. Appl Environ Microbiol 69:1581–1588. https://doi.org/10.1128/AEM.69.3.1581-1588.2003
Park N-H, Shin K-H, Kang MK (2017) 34 - Antifungal and antiviral agents. In: Dowd FJ, Johnson BS, Mariotti AJ (eds) Pharmacology and therapeutics for dentistry (Seventh Edition). Mosby, pp 488–503
Patron NJ, Waller RF, Cozijnsen AJ et al (2007) Origin and distribution of epipolythiodioxopiperazine (ETP) gene clusters in filamentous ascomycetes. BMC Evol Biol 7:174. https://doi.org/10.1186/1471-2148-7-174
Paulussen C, Hallsworth JE, Álvarez-Pérez S et al (2017) Ecology of aspergillosis: insights into the pathogenic potency of Aspergillus fumigatus and some other Aspergillus species. Microb Biotechnol 10:296–322. https://doi.org/10.1111/1751-7915.12367
Perez-Cuesta U, Aparicio-Fernandez L, Guruceaga X et al (2020) Melanin and pyomelanin in Aspergillus fumigatus: from its genetics to host interaction. Int Microbiol 23:55–63. https://doi.org/10.1007/s10123-019-00078-0
Petrikkos G, Skiada A (2007) Recent advances in antifungal chemotherapy. Int J Antimicrob Agents 30:108–117. https://doi.org/10.1016/j.ijantimicag.2007.03.009
Pihet M, Vandeputte P, Tronchin G et al (2009) Melanin is an essential component for the integrity of the cell wall of Aspergillus fumigatus conidia. BMC Microbiol 9:177. https://doi.org/10.1186/1471-2180-9-177
Pombeiro-Sponchiado SR, Sousa GS, R. Andrade JC, et al (2017) Production of melanin pigment by fungi and its biotechnological applications. Melanin 47-64.https://doi.org/10.5772/67375
Rambach G, Blum G, Latgé J-P et al (2015) Identification of Aspergillus fumigatus Surface components that mediate interaction of conidia and hyphae with human platelets. J Infect Dis 212:1140–1149. https://doi.org/10.1093/infdis/jiv191
Reichert-Lima F, Lyra L, Pontes L et al (2018) Surveillance for azoles resistance in Aspergillus spp. highlights a high number of amphotericin B-resistant isolates. Mycoses 61:360–365. https://doi.org/10.1111/myc.12759
Ries LNA, Steenwyk JL, de Castro PA et al (2019) Nutritional heterogeneity among Aspergillus fumigatus strains has consequences for virulence in a strain- and host-dependent manner. Front Microbiol 10:1–20. https://doi.org/10.3389/fmicb.2019.00854
Rocha MC, Fabri JHTM, Franco de Godoy K et al (2016) Aspergillus fumigatus MADS-Box transcription factor rlmA is required for regulation of the cell wall integrity and virulence. G3 (Bethesda) 6:2983–3002. https://doi.org/10.1534/g3.116.031112
Scharf DH, Remme N, Heinekamp T et al (2010) Transannular disulfide formation in gliotoxin biosynthesis and its role in self-resistance of the human pathogen Aspergillus fumigatus. J Am Chem Soc 132:10136–10141. https://doi.org/10.1021/ja103262m
Scharf DH, Remme N, Habel A et al (2011) A dedicated glutathione S-transferase mediates carbon-sulfur bond formation in gliotoxin biosynthesis. J Am Chem Soc 133:12322–12325. https://doi.org/10.1021/ja201311d
Scharf DH, Chankhamjon P, Scherlach K et al (2012) Epidithiol formation by an unprecedented twin carbon–sulfur lyase in the gliotoxin pathway. Angew Chem Int Ed 51:10064–10068. https://doi.org/10.1002/anie.201205041
Scharf DH, Habel A, Heinekamp T et al (2014) Opposed effects of enzymatic gliotoxin n- and s-methylations. J Am Chem Soc 136:11674–11679. https://doi.org/10.1021/ja5033106
Schrettl M, Bignell E, Kragl C et al (2004) Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence. J Exp Med 200:1213–1219. https://doi.org/10.1084/jem.20041242
Schrettl M, Bignell E, Kragl C et al (2007) Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection. PLoS Pathog 3:e128. https://doi.org/10.1371/journal.ppat.0030128
Schrettl M, Kim HS, Eisendle M et al (2008) SreA-mediated iron regulation in Aspergillus fumigatus. Mol Microbiol 70:27–43. https://doi.org/10.1111/j.1365-2958.2008.06376.x
Schrettl M, Beckmann N, Varga J et al (2010) HapX-mediated adaption to iron starvation is crucial for virulence of Aspergillus fumigatus. PLoS Pathog 6:e1001124. https://doi.org/10.1371/journal.ppat.1001124
Schrettl M, Carberry S, Kavanagh K et al (2010) Self-protection against gliotoxin—a component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLoS Pathog 6:e1000952. https://doi.org/10.1371/journal.ppat.1000952
Scorzoni L, de Paula E, Silva ACA, Marcos CM et al (2017) Antifungal therapy: new advances in the understanding and treatment of mycosis. Front Microbiol 8:36. https://doi.org/10.3389/fmicb.2017.00036
Shah DT, Larsen B (1991) Clinical isolates of yeast produce a gliotoxin-like substance. Mycopathologia 116:203–208. https://doi.org/10.1007/BF00436836
Shankar J, Tiwari S, Shishodia SK et al (2018) Molecular insights into development and virulence determinants of aspergilli: a proteomic perspective. Front Cell Infect Microbiol 8:1–15. https://doi.org/10.3389/fcimb.2018.00180
Song JC, Stevens DA (2016) Caspofungin: pharmacodynamics, pharmacokinetics, clinical uses and treatment outcomes. Crit Rev Microbiol 42:813–846. https://doi.org/10.3109/1040841X.2015.1068271
Song J, Zhai P, Zhang Y et al (2016) The Aspergillus fumigatus damage resistance protein family co-ordinately regulates ergosterol biosynthesis and azole susceptibility. mBio 7:e01919-01915. https://doi.org/10.1128/mBio.01919-15
Song J, Li R, Jiang J (2019) Copper homeostasis in Aspergillus fumigatus: opportunities for therapeutic development. Front Microbiol 10:774. https://doi.org/10.3389/fmicb.2019.00774
Sugareva V, Härtl A, Brock M et al (2006) Characterisation of the laccase-encoding gene abr2 of the dihydroxynaphthalene-like melanin gene cluster of Aspergillus fumigatus. Arch Microbiol 186:345–355. https://doi.org/10.1007/s00203-006-0144-2
Sugui JA, Pardo J, Chang YC et al (2007) Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone. Eukaryot Cell 6:1562–1569. https://doi.org/10.1128/EC.00141-07
Taborda CP, da Silva MB, Nosanchuk JD, Travassos LR (2008) Melanin as a virulence factor of Paracoccidioides brasiliensis and other dimorphic pathogenic fungi: a minireview. Mycopathologia 165:331–339. https://doi.org/10.1007/s11046-007-9061-4
Tatsumi Y, Nagashima M, Shibanushi T et al (2013) Mechanism of action of efinaconazole, a novel triazole antifungal agent. Antimicrob Agents Chemother 57:2405–2409. https://doi.org/10.1128/AAC.02063-12
Thywißen A, Heinekamp T, Dahse H-M et al (2011) Conidial dihydroxynaphthalene melanin of the human pathogenic fungus Aspergillus fumigatus interferes with the host endocytosis pathway. Front Microbiol 2:96. https://doi.org/10.3389/fmicb.2011.00096
Tissot F, Agrawal S, Pagano L et al (2017) ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica 102:433–444. https://doi.org/10.3324/haematol.2016.152900
Upadhyay S, Xu X, Lin X (2016) Interactions between melanin enzymes and their atypical recruitment to the secretory pathway by palmitoylation. mBio 7:1–12. https://doi.org/10.1128/mBio.01925-16
Upadhyay S, Xu X, Lowry D et al (2016) Subcellular compartmentalization and trafficking of the biosynthetic machinery for fungal melanin. Cell Rep 14:2511–2518. https://doi.org/10.1016/j.celrep.2016.02.059
Valiante V, Heinekamp T, Jain R et al (2008) The mitogen-activated protein kinase MpkA of Aspergillus fumigatus regulates cell wall signalling and oxidative stress response. Fungal Genet Biol 45:618–627. https://doi.org/10.1016/j.fgb.2007.09.006
Valiante V, Macheleidt J, Föge M, Brakhage AA (2015) The Aspergillus fumigatus cell wall integrity signalling pathway: drug target, compensatory pathways, and virulence. Front Microbiol 6:325. https://doi.org/10.3389/fmicb.2015.00325
Valsecchi I, Dupres V, Stephen-Victor E et al (2017) Role of hydrophobins in Aspergillus fumigatus. J Fungi (Basel) 4:1–19. https://doi.org/10.3390/jof4010002
Valsecchi I, Lai JI, Stephen-Victor E et al (2019) Assembly and disassembly of Aspergillus fumigatus conidial rodlets. The Cell Surface 5:100023. https://doi.org/10.1016/j.tcsw.2019.100023
van de Veerdonk FL, Gresnigt MS, Romani L et al (2017) Aspergillus fumigatus morphology and dynamic host interactions. Nat Rev Microbiol 15:661–674. https://doi.org/10.1038/nrmicro.2017.90
van Duin D, Casadevall A, Nosanchuk JD (2002) Melanization of Cryptococcus neoformans and Histoplasma capsulatum reduces their susceptibilities to amphotericin b and caspofungin. Antimicrob Agents Chemother 46:3394–3400. https://doi.org/10.1128/AAC.46.11.3394-3400.2002
Verweij PE, Chowdhary A, Melchers WJG, Meis JF (2016) Azole resistance in Aspergillus fumigatus: Can we retain the clinical use of mold-active antifungal azoles? Clin Infect Dis 62:362–368. https://doi.org/10.1093/cid/civ885
Voltersen V, Blango MG, Herrmann S et al (2018) Proteome analysis reveals the conidial surface protein CcpA essential for virulence of the pathogenic fungus Aspergillus fumigatus. mBio 9:1–18. https://doi.org/10.1128/mBio.01557-18
Warris A, Ballou ER (2019) Oxidative responses and fungal infection biology. Semin Cell Dev Biol 89:34–46. https://doi.org/10.1016/j.semcdb.2018.03.004
Webb BJ, Ferraro JP, Rea S et al (2018) Epidemiology and clinical features of invasive fungal infection in a US health care network. Open Forum Infect Dis 5:1–8. https://doi.org/10.1093/ofid/ofy187
Wong-Beringer A, Jacobs RA, Guglielmo BJ (1998) Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin Infect Dis 27:603–618. https://doi.org/10.1086/514704
Yasmin S, Alcazar-Fuoli L, Grundlinger M et al (2012) Mevalonate governs interdependency of ergosterol and siderophore biosynthesis in the fungal pathogen Aspergillus fumigatus. Proc Natl Acad Sci 109:E497–E504. https://doi.org/10.1073/pnas.1106399108
Yoshimi A, Miyazawa K, Abe K (2016) Cell wall structure and biogenesis in Aspergillus species. Biosci Biotechnol Biochem 80:1700–1711. https://doi.org/10.1080/09168451.2016.1177446
Zacharias CA, Sheppard DC (2019) The role of Aspergillus fumigatus polysaccharides in host-pathogen interactions. Curr Opin Microbiol 52:20–26. https://doi.org/10.1016/j.mib.2019.04.006
Zaragoza O (2019) Basic principles of the virulence of Cryptococcus. Virulence 10:490–501. https://doi.org/10.1080/21505594.2019.1614383
Zeng Q, Zhang Z, Chen P et al (2019) In vitro and in vivo efficacy of a synergistic combination of itraconazole and verapamil against Aspergillus fumigatus. Front Microbiol 10:1–12. https://doi.org/10.3389/fmicb.2019.01266
Funding
The authors would like to thank the Department of Science and Technology-Science and Engineering Research Board (DST-SERB) (EMR/2016/005752) New Delhi, Govt. of India, for their financial support.
Author information
Authors and Affiliations
Contributions
Lovely Gupta and Shanu Hoda performed literature search, recreated figures and drafted the manuscript; Maansi Vermani critically reviewed the manuscript and corrected; and Pooja Vijayaraghavan conceptualised the idea as well as critically analysed the manuscript.
Corresponding author
Ethics declarations
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Conflict of interest
The authors declare no conflict of interest.
Additional information
Section editor: Marc Stadler.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gupta, L., Hoda, S., Vermani, M. et al. Understanding the fundamental role of virulence determinants to combat Aspergillus fumigatus infections: exploring beyond cell wall. Mycol Progress 20, 365–380 (2021). https://doi.org/10.1007/s11557-021-01677-w
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11557-021-01677-w