Pathogenicity and virulence of Aspergillus fumigatus

Figures & data

Figure 1. A. fumigatus lifecycle both in the environment and a human host. A. fumigatus can enter an asexual (blue) or sexual (red) reproductive cycle. During the sexual cycle, the fungus undergoes meiotic recombination to form the cleistothecium, which contains ascospores. Dead plant matter is an ideal environmental niche for C. fumigatus to sporulate and grow. During the asexual cycle, the mycelium generates spores, which can be aerially dispersed. Some of these conidia land in a new ecological niche, while others are inhaled by humans and can cause disease (green).

Table 1. A selection of A. fumigatus genes and molecules involved in virulence. Representative genes from a range of categories including adherence, thermotolerance, nutrition/metabolism, cell wall integrity, interaction with the host immune system and stress response have been highlighted.

PROCESS	GENE/MOLECULE	FUNCTION	REFERENCES
Adherence	aspf2	Laminin binding	[111]
	cspA	Extracellular matrix binding	[112]
	AfCalAp	Laminin binding	[113]
	GAG	Multi-substrate binding Biofilm formation	[114]
Thermotolerance	afmnt1	Mannosyltransferase (cell wall modification)	[115]
	cgrA/	Ribosome biogenesis	[116]
Nutrition/metabolism	alp/aspf13	Serine protease, degradation of host proteins	[117]
	creA	Regulation of carbon catabolite repression	[118]
	rhbA	Regulation of nitrogen signalling	[119]
	cpcA	Master regulator of amino acid biosynthesis	[120]
	hcsA, aroC, trpA, ilv3A, ilv3B, hisB, metH, mecA, alaA, lysF	Amino acid biosynthesis	Reviewed in [121–123]
	sidA, sidD, sidF, sidH, sidI, sidC	Siderophore biosynthesis, iron uptake	Reviewed in [124]
	hapX	Regulation of iron homoeostasis	[125]
	zrfC	Zinc uptake	[126]
	zafA	Regulation of zinc homoeostasis	[127]
	mcsA	Detoxification of fungal metabolites	[128]
	pabaA	Biosynthesis of folate	[129]
Cell wall integrity	chsG	Chitin biosynthesis	[130]
	glfA	Galactomannan biosynthesis	[131]
	afmnt1	Mannosyltransferase (cell wall modification)	[115]
Interaction with the host immune system	pksP	Melanin biosynthesis	Reviewed in [132]
	cat1/cat2/sod1/sod2/sod3	ROS detoxification	[133,134]
	gliP	Gliotoxin biosynthesis	Reviewed in [12]
	rglT	Regulation of gliotoxin biosynthesis and self-protection	[135]
	AfBIR1	Regulation of programmed cell death	[136]
Stress response	pkaC1	Stress and carbon source sensing	[123]
	pkaR	Regulation of PKA	[137]
	mkk2	Cell wall damage sensing	[138]
	sskB	Osmotic stress sensing	[113]
	ptcB	Regulation of osmotic stress response	[139]
	schA	Regulation of osmotic stress response	[140]
	cna	Calcium signalling	[141]
	crzA	Calcium signalling	[142]
	ZipD	Calcium signalling	[143]
	srbA	Oxygen sensor	[144]
	sskA	Regulation of osmotic stress	[145]
	hrmA	Induction of hypoxic phenotype	[146]
	HIF-1α	Immune cell activation	[147]
	ireA	Mediator of ER stress via UPR pathway	[148]
	hacA	Mediator of ER stress via UPR pathway	[149]
	pacC	Alkaline pH response	[150]
Hyphal Growth	rasB	Germination and hyphal growth	[151]

Figure 2. Diagram of innate immune response against Aspergillus fumigatus. This figure schematically represents an overview of the information presented in this review regarding epithelial cell, macrophage, neutrophil, and dendritic cell interactions with A. fumigatus.

Banerjee B, Greenberger PA, Fink JN, et al. Immunological characterization of Asp f 2, a major allergen from Aspergillus fumigatus associated with allergic bronchopulmonary aspergillosis. Infect Immun. 1998;66(11):5175–5182.

 PubMed Web of Science ®Google Scholar

Levdansky E, Romano J, Shadkchan Y, et al. Coding tandem repeats generate diversity in Aspergillus fumigatus genes. Eukaryot Cell. 2007;6(8):13801391. PubMed: 17557878.

 Google Scholar

Upadhyay SK, Mahajan L, Ramjee S, et al. Identification and characterization of a laminin-binding protein of Aspergillus fumigatus: extracellular thaumatin domain protein (AfCalap). J Med Microbiol. 2009;58(6):714–722.

 PubMed Web of Science ®Google Scholar

Speth C, Rambach G, Lass-Flörl C, et al. Galactosaminogalactan (GAG) and its multiple roles in Aspergillus pathogenesis. Virulence. 2019;10(1):976–983.

 PubMed Web of Science ®Google Scholar

Wagener J, Echtenacher B, Rohde M, et al. The putative alpha-1,2-mannosyltransferase AfMnt1 of the opportunistic fungal pathogen Aspergillus fumigatus is required for cell wall stability and full virulence. Eukaryot Cell. 2008;7(10):1661–1673.

 PubMedGoogle Scholar

Bhabhra R, Miley MD, Mylonakis E, et al. Disruption of the Aspergillus fumigatus gene encoding nucleolar protein CgrA impairs thermotolerant growth and reduces virulence. Infect Immun. 2004 Aug;72(8):4731–4740. DOI:10.1128/IAI.72.8.4731-4740.2004.

 PubMed Web of Science ®Google Scholar

Kolattukudy PE, Lee JD, Rogers LM, et al. Evidence for possible involvement of an elastolytic serine protease in aspergillosis. Infect Immun. 1993;61(6):2357–2368.

 PubMed Web of Science ®Google Scholar

Beattie SR, Mark KMK, Thammahong A, et al. Filamentous fungal carbon catabolite repression supports metabolic plasticity and stress responses essential for disease progression. PLoS Pathogen. 2017;13(4):e1006340.

 PubMed Web of Science ®Google Scholar

Panepinto JC, Oliver BG, Fortwendel JR, et al. Deletion of the Aspergillus fumigatus gene encoding the Ras-related protein RhbA reduces virulence in a model of invasive pulmonary aspergillosis. Infect Immun. 2003;71(5):2819–2826.

 PubMed Web of Science ®Google Scholar

Krappmann S, Bignell EM, Reichard U, et al. The Aspergillus fumigatus transcriptional activator CpcA contributes significantly to the virulence of this fungal pathogen. Mol Microbiol. 2004;52(3):785–799.

 PubMed Web of Science ®Google Scholar

Schrettl M, Bignell E, Kragl C, et al. Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence. J Exp Med. 2004;200(9):1213–1219.

 PubMed Web of Science ®Google Scholar

Schrettl M, Haas H. Iron homeostasis–achilles’ heel of Aspergillus fumigatus? Curr Opin Microbiol. 2011;14(4):400–405.

 PubMed Web of Science ®Google Scholar

Amich J, Vicente Franqueira R, Leal F, et al. Aspergillus fumigatus survival in alkaline and extreme zinc-limiting environments relies on the induction of a zinc homeostasis system encoded by the zrfc and aspf2 genes. Eukaryotic Cell. 2010;9(3):424–437.

 PubMedGoogle Scholar

Moreno MÁ, Ibrahim-Granet O, Vicentefranqueira R, et al. The regulation of zinc homeostasis by the ZafA transcriptional activator is essential for Aspergillus fumigatus virulence. Mol Microbiol. 2007;64(5):1182–1197.

 PubMed Web of Science ®Google Scholar

Schlachter CR, Klapper V, Radford T, et al. Comparative studies of aspergillus fumigatus 2-methylcitrate synthase and human citrate synthase. Biol Chem. 2019;400(12):1567–1581.

 PubMed Web of Science ®Google Scholar

Brown JS, Aufauvre-Brown A, Brown J, et al. Signature-tagged and directed mutagenesis identify PABA synthetase as essential for aspergillus fumigatus pathogenicity. Mol Microbiol. 2002;36(6):1371–1380.

 Web of Science ®Google Scholar

Mellado E, Aufauvre-Brown A, Gow NA, et al. The Aspergillus fumigatus chsC and chsG genes encode class III chitin synthases with different functions. Mol Microbiol. 1996;20(3):667–679.

 PubMed Web of Science ®Google Scholar

Schmalhorst PS, Krappmann S, Vervecken W, et al. Contribution of galactofuranose to the virulence of the opportunistic pathogen Aspergillus fumigatus. Eukaryot Cell. 2008;7(8):1268–1277.

 PubMedGoogle Scholar

Chamilos G, Carvalho A. Aspergillus fumigatus DHN-Melanin. Curr Top Microbiol Immunol. 2020;425:17–28.

 PubMed Web of Science ®Google Scholar

Calera JA, Paris S, Monod M, et al. Cloning and disruption of the antigenic catalase gene of Aspergillus fumigatus’. Infect Immun. 1997;65(11):4718–4724.

 PubMed Web of Science ®Google Scholar

Lambou K, Lamarre C, Beau R, et al. Functional analysis of the superoxide dismutase family in Aspergillus fumigatus. Mol Microbiol. 2010;75(4):910–923.

 PubMed Web of Science ®Google Scholar

Kwon-Chung KJ, Sugui JA. What do we know about the role of gliotoxin in the pathobiology of Aspergillus fumigatus? Med Mycol. 2009;47(Suppl 1):S97–103.

 PubMed Web of Science ®Google Scholar

Ries LNA, Pardeshi L, Dong Z, et al. The Aspergillus fumigatus transcription factor RglT is important for gliotoxin biosynthesis and self-protection, and virulence. PLOS Pathog. 2020;16(7):e1008645.

 PubMed Web of Science ®Google Scholar

Shlezinger N, Irmer H, Dhingra S, et al. Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death. Science. 2017;357(6355):1037–1041.

 PubMed Web of Science ®Google Scholar

Liebmann B, Muller M, Braun A, et al. The cyclic AMP-dependent protein kinase a network regulates development and virulence in Aspergillus fumigatus. Infect Immun. 2004;72(9):5193–5203.

 PubMed Web of Science ®Google Scholar

Zhao W, Panepinto JC, Fortwendel JR, et al. Deletion of the regulatory subunit of protein kinase a in Aspergillus fumigatus alters morphology, sensitivity to oxidative damage, and virulence. Infect Immun. 2006;74(8):4865–4874.

 PubMed Web of Science ®Google Scholar

Dirr F, Echtenacher B, Heesemann J, et al. AfMkk2 is required for cell wall integrity signaling, adhesion, and full virulence of the human pathogen Aspergillus fumigatus. Int J Med Microbiol. 2010;300(7):496–502.

 PubMed Web of Science ®Google Scholar

Winkelströter LK, Bom VL, de Castro PA, et al. High osmolarity glycerol response PtcB phosphatase is important for Aspergillus fumigatus virulence. Mol Microbiol. 2015;96(1):42–54.

 PubMed Web of Science ®Google Scholar

Alves de Castro P, Dos Reis TF, Dolan SK, et al. The Aspergillus fumigatus SchA SCH9 kinase modulates SakA HOG1 MAP kinase activity and it is essential for virulence. Mol Microbiol. 2016 Nov;102(4):642–671. DOI:10.1111/mmi.13484.

 PubMed Web of Science ®Google Scholar

Steinbach WJ, Cramer RA Jr, Perfect BZ, et al. Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus. Eukaryot Cell. 2006;5(7):1091–1103.

 PubMedGoogle Scholar

Soriani FM, Malavazi I, Da Silva Ferreira ME, et al. Functional characterization of the Aspergillus fumigatus CRZ1 homologue, CrzA. Mol Microbiol. 2008;67(6):1274–1291.

 PubMed Web of Science ®Google Scholar

de Castro P, Colabardini A, Manfiolli A, et al. Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance. PLoS Genet. 2019;15(12):e1008551.

 PubMed Web of Science ®Google Scholar

Willger SD, Puttikamonkul S, Kim KH, et al. A sterol-regulatory element binding protein is required for cell polarity, hypoxia adaptation, azole drug resistance, and virulence in Aspergillus fumigatus. PLOS Pathog. 2008;4(11):e1000200.

 PubMed Web of Science ®Google Scholar

Kirkland M, Stannard M, Kowalski C, et al. Host lung environment limits Aspergillus fumigatus germination through an SskA-Dependent Signaling Response. mSphere. 2021;6(6). DOI:10.1128/msphere.00922-21

 PubMed Web of Science ®Google Scholar

Kowalski C, Kerkaert J, Liu K, et al. Fungal biofilm morphology impacts hypoxia fitness and disease progression. Nat Microbiol. 2019;4(12):2430–2441.

 PubMed Web of Science ®Google Scholar

Nizet V, Johnson R. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol. 2009;9(9):609–617.

 PubMed Web of Science ®Google Scholar

Feng X, Krishnan K, Richie DL, et al. Haca-independent functions of the ER stress sensor IREA synergize with the canonical upr to influence virulence traits in aspergillus fumigatus. PLOS Pathogens. 2011;7(10):10.

 Web of Science ®Google Scholar

Mulder HJ, Saloheimo M, Penttilä M, et al. The transcription factor HACA mediates the unfolded protein response in aspergillus niger, and up-regulates its own transcription. Mol Genet Genomic. 2004;271(2):130–140.

 PubMed Web of Science ®Google Scholar

Bertuzzi M, Schrettl M, Alcazar-Fuoli L, et al. The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis. 16 PLOS Pathog. 2014;101:e1004413. 10.1371/journal.ppat.1004413

 PubMedGoogle Scholar

Fortwendel JR, Zhao W, Bhabhra R, et al. A fungus-specific ras homolog contributes to the hyphal growth and virulence of aspergillus fumigatus. Eukaryotic Cell. 2005;4(12):1982–1989.

 PubMedGoogle Scholar