Aspergillus fumigatus

Aspergillus fumigatus has a stable haploid genome of 29.4 million base pairs. The genome sequences of three Aspergillus species—Aspergillus fumigatus, Aspergillus nidulans, and Aspergillus oryzae—were published in Nature in December 2005.{{cite journal | vauthors = Galagan JE, Calvo SE, Cuomo C, Ma LJ, Wortman JR, Batzoglou S, Lee SI, Baştürkmen M, Spevak CC, Clutterbuck J, Kapitonov V, Jurka J, Scazzocchio C, Farman M, Butler J, Purcell S, Harris S, Braus GH, Draht O, Busch S, D'Enfert C, Bouchier C, Goldman GH, Bell-Pedersen D, Griffiths-Jones S, Doonan JH, Yu J, Vienken K, Pain A, Freitag M, Selker EU, Archer DB, Peñalva MA, Oakley BR, Momany M, Tanaka T, Kumagai T, Asai K, Machida M, Nierman WC, Denning DW, Caddick M, Hynes M, Paoletti M, Fischer R, Miller B, Dyer P, Sachs MS, Osmani SA, Birren BW | display-authors = 6 | title = Sequencing of Aspergillus nidulans and comparative analysis with A. fumigatus and A. oryzae | journal = Nature | volume = 438 | issue = 7071 | pages = 1105–15 | date = December 2005 | pmid = 16372000 | doi = 10.1038/nature04341 | bibcode = 2005Natur.438.1105G | doi-access = free }}{{cite journal | vauthors = Machida M, Asai K, Sano M, Tanaka T, Kumagai T, Terai G, Kusumoto K, Arima T, Akita O, Kashiwagi Y, Abe K, Gomi K, Horiuchi H, Kitamoto K, Kobayashi T, Takeuchi M, Denning DW, Galagan JE, Nierman WC, Yu J, Archer DB, Bennett JW, Bhatnagar D, Cleveland TE, Fedorova ND, Gotoh O, Horikawa H, Hosoyama A, Ichinomiya M, Igarashi R, Iwashita K, Juvvadi PR, Kato M, Kato Y, Kin T, Kokubun A, Maeda H, Maeyama N, Maruyama J, Nagasaki H, Nakajima T, Oda K, Okada K, Paulsen I, Sakamoto K, Sawano T, Takahashi M, Takase K, Terabayashi Y, Wortman JR, Yamada O, Yamagata Y, Anazawa H, Hata Y, Koide Y, Komori T, Koyama Y, Minetoki T, Suharnan S, Tanaka A, Isono K, Kuhara S, Ogasawara N, Kikuchi H | display-authors = 6 | title = Genome sequencing and analysis of Aspergillus oryzae | journal = Nature | volume = 438 | issue = 7071 | pages = 1157–61 | date = December 2005 | pmid = 16372010 | doi = 10.1038/nature04300 | bibcode = 2005Natur.438.1157M | doi-access = free }}

Aspergillus fumigatus is the most frequent cause of invasive fungal infection in immunosuppressed individuals, which include patients receiving immunosuppressive therapy for autoimmune or neoplastic disease, organ transplant recipients, and AIDS patients.{{cite journal | vauthors = Ben-Ami R, Lewis RE, Kontoyiannis DP|author-link3=Dimitrios Kontoyiannis | title = Enemy of the (immunosuppressed) state: an update on the pathogenesis of Aspergillus fumigatus infection | journal = British Journal of Haematology | volume = 150 | issue = 4 | pages = 406–17 | date = August 2010 | pmid = 20618330 | doi = 10.1111/j.1365-2141.2010.08283.x |s2cid=28216163 | doi-access = free }} A. fumigatus primarily causes invasive infection in the lung and represents a major cause of morbidity and mortality in these individuals.{{cite journal | vauthors = Hohl TM, Feldmesser M | title = Aspergillus fumigatus: principles of pathogenesis and host defense | journal = Eukaryotic Cell | volume = 6 | issue = 11 | pages = 1953–63 | date = November 2007 | pmid = 17890370 | pmc = 2168400 | doi = 10.1128/EC.00274-07 }} Additionally, A. fumigatus can cause chronic pulmonary infections, allergic bronchopulmonary aspergillosis, or allergic disease in immunocompetent hosts.{{cite journal | vauthors = Segal BH | title = Aspergillosis | journal = The New England Journal of Medicine | volume = 360 | issue = 18 | pages = 1870–84 | date = April 2009 | pmid = 19403905 | doi = 10.1056/NEJMra0808853 }}

Inhalational exposure to airborne conidia is continuous due to their ubiquitous distribution in the environment. However, in healthy individuals, the innate immune system is an efficacious barrier to A. fumigatus infection. A large portion of inhaled conidia are cleared by the mucociliary action of the respiratory epithelium. Due to the small size of conidia, many of them deposit in alveoli, where they interact with epithelial and innate effector cells. Alveolar macrophages phagocytize and destroy conidia within their phagosomes. Epithelial cells, specifically type II pneumocytes, also internalize conidia which traffic to the lysosome where ingested conidia are destroyed.{{cite journal | vauthors = Filler SG, Sheppard DC | title = Fungal invasion of normally non-phagocytic host cells | journal = PLOS Pathogens | volume = 2 | issue = 12 | pages = e129 | date = December 2006 | pmid = 17196036 | pmc = 1757199 | doi = 10.1371/journal.ppat.0020129 | doi-access = free }} First line immune cells also serve to recruit neutrophils and other inflammatory cells through release of cytokines and chemokines induced by ligation of specific fungal motifs to pathogen recognition receptors. Neutrophils are essential for aspergillosis resistance, as demonstrated in neutropenic individuals, and are capable of sequestering both conidia and hyphae through distinct, non-phagocytic mechanisms. Hyphae are too large for cell-mediated internalization, and thus neutrophil-mediated NADPH-oxidase induced damage represents the dominant host defense against hyphae. In addition to these cell-mediated mechanisms of elimination, antimicrobial peptides secreted by the airway epithelium contribute to host defense. The fungus and its polysaccharides have ability to regulate the functions of dendritic cells by

Wnt-β-Catenin signaling pathway to induce PD-L1 and to promote regulatory T cell responses{{cite journal |vauthors=Karnam A, Bonam SR, Rambabu N, Wong SS, Aimanianda V, Bayry J |title=Wnt-β-Catenin Signaling in Human Dendritic Cells Mediates Regulatory T-Cell Responses to Fungi via the PD-L1 Pathway. |journal=mBio |date=November 16, 2021 |volume=12 |issue=6 |page=e0282421 |doi=10.1128/mBio.02824-21 |doi-access=free |pmid=34781737|pmc=8593687 }}{{cite journal |vauthors=Stephen-Victor E, Karnam A, Fontaine T, Beauvais A, Das M, Hegde P, Prakhar P, Holla S, Balaji KN, Kaveri SV, Latgé JP, Aimanianda V, Bayry J |title=Aspergillus fumigatus Cell Wall α-(1,3)-Glucan Stimulates Regulatory T-Cell Polarization by Inducing PD-L1 Expression on Human Dendritic Cells |journal=J Infect Dis |date=December 5, 2017 |volume=216 |issue=10 |pages=1281–1294 |doi=10.1093/infdis/jix469 |doi-access=free |pmid=28968869}}

Image:Aspergillus fumigatus Invasive Disease Mechanism Diagram.jpg

Immunosuppressed individuals are susceptible to invasive A. fumigatus infection, which most commonly manifests as invasive pulmonary aspergillosis. Inhaled conidia that evade host immune destruction are the progenitors of invasive disease. These conidia emerge from dormancy and make a morphological switch to hyphae by germinating in the warm, moist, nutrient-rich environment of the pulmonary alveoli. Germination occurs both extracellularly or in type II pneumocyte endosomes containing conidia. Following germination, filamentous hyphal growth results in epithelial penetration and subsequent penetration of the vascular endothelium. The process of angioinvasion causes endothelial damage and induces a proinflammatory response, tissue factor expression and activation of the coagulation cascade. This results in intravascular thrombosis and localized tissue infarction, however, dissemination of hyphal fragments is usually limited. Dissemination through the blood stream only occurs in severely immunocompromised individuals.

As is common with tumor cells and other pathogens, the invasive hyphae of A. fumigatus encounters hypoxic (low oxygen levels, ≤ 1%) micro-environments at the site of infection in the host organism.{{cite journal | vauthors = Grahl N, Cramer RA | title = Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi? | journal = Medical Mycology | volume = 48 | issue = 1 | pages = 1–15 | date = February 2010 | pmid = 19462332 | pmc = 2898717 | doi = 10.3109/13693780902947342 }}{{cite journal | vauthors = Grahl N, Shepardson KM, Chung D, Cramer RA | title = Hypoxia and fungal pathogenesis: to air or not to air? | journal = Eukaryotic Cell | volume = 11 | issue = 5 | pages = 560–70 | date = May 2012 | pmid = 22447924 | pmc = 3346435 | doi = 10.1128/EC.00031-12 }}{{cite journal | vauthors = Wezensky SJ, Cramer RA | title = Implications of hypoxic microenvironments during invasive aspergillosis | journal = Medical Mycology | volume = 49 | issue = Suppl 1 | pages = S120–4 | date = April 2011 | pmid = 20560863 | pmc = 2951492 | doi = 10.3109/13693786.2010.495139 }} Current research suggests that upon infection, necrosis and inflammation cause tissue damage which decreases available oxygen concentrations due to a local reduction in perfusion, the passaging of fluids to organs. In A. fumigatus specifically, secondary metabolites have been found to inhibit the development of new blood vessels leading to tissue damage, the inhibition of tissue repair, and ultimately localized hypoxic micro-environments. The exact implications of hypoxia on fungal pathogenesis is currently unknown, however these low oxygen environments have long been associated with negative clinical outcomes. Due to the significant correlations identified between hypoxia, fungal infections, and negative clinical outcomes, the mechanisms by which A. fumigatus adapts in hypoxia is a growing area of focus for novel drug targets.

Two highly characterized sterol-regulatory element binding proteins, SrbA and SrbB, along with their processing pathways, have been shown to impact the fitness of A. fumigatus in hypoxic conditions. The transcription factor SrbA is the master regulator in the fungal response to hypoxia in vivo and is essential in many biological processes including iron homeostasis, antifungal azole drug resistance, and virulence.{{cite journal | vauthors = Willger SD, Puttikamonkul S, Kim KH, Burritt JB, Grahl N, Metzler LJ, Barbuch R, Bard M, Lawrence CB, Cramer RA | title = A sterol-regulatory element binding protein is required for cell polarity, hypoxia adaptation, azole drug resistance, and virulence in Aspergillus fumigatus | journal = PLOS Pathogens | volume = 4 | issue = 11 | pages = e1000200 | date = November 2008 | pmid = 18989462 | pmc = 2572145 | doi = 10.1371/journal.ppat.1000200 | doi-access = free }} Consequently, the loss of SrbA results in an inability for A. fumigatus to grow in low iron conditions, a higher sensitivity to anti-fungal azole drugs, and a complete loss of virulence in IPA (invasive pulmonary aspergillosis) mouse models.{{cite journal | vauthors = Chung D, Barker BM, Carey CC, Merriman B, Werner ER, Lechner BE, Dhingra S, Cheng C, Xu W, Blosser SJ, Morohashi K, Mazurie A, Mitchell TK, Haas H, Mitchell AP, Cramer RA | title = ChIP-seq and in vivo transcriptome analyses of the Aspergillus fumigatus SREBP SrbA reveals a new regulator of the fungal hypoxia response and virulence | journal = PLOS Pathogens | volume = 10 | issue = 11 | pages = e1004487 | date = November 2014 | pmid = 25375670 | pmc = 4223079 | doi = 10.1371/journal.ppat.1004487 | doi-access = free }} SrbA knockout mutants do not show any signs of in vitro growth in low oxygen, which is thought to be associated with the attenuated virulence. SrbA functionality in hypoxia is dependent upon an upstream cleavage process carried out by the proteins RbdB, SppA, and Dsc A-E.{{cite journal | vauthors = Dhingra S, Kowalski CH, Thammahong A, Beattie SR, Bultman KM, Cramer RA | title = RbdB, a Rhomboid Protease Critical for SREBP Activation and Virulence in Aspergillus fumigatus | journal = mSphere | volume = 1 | issue = 2 | date = 2016 | pmid = 27303716 | pmc = 4863583 | doi = 10.1128/mSphere.00035-16 }}{{cite journal | vauthors = Bat-Ochir C, Kwak JY, Koh SK, Jeon MH, Chung D, Lee YW, Chae SK | title = The signal peptide peptidase SppA is involved in sterol regulatory element-binding protein cleavage and hypoxia adaptation in Aspergillus nidulans | journal = Molecular Microbiology | volume = 100 | issue = 4 | pages = 635–55 | date = May 2016 | pmid = 26822492 | doi = 10.1111/mmi.13341 | doi-access = free }}{{cite journal | vauthors = Willger SD, Cornish EJ, Chung D, Fleming BA, Lehmann MM, Puttikamonkul S, Cramer RA | title = Dsc orthologs are required for hypoxia adaptation, triazole drug responses, and fungal virulence in Aspergillus fumigatus | journal = Eukaryotic Cell | volume = 11 | issue = 12 | pages = 1557–67 | date = December 2012 | pmid = 23104569 | pmc = 3536281 | doi = 10.1128/EC.00252-12 }} SrbA is cleaved from an endoplasmic reticulum residing 1015 amino acid precursor protein to a 381 amino acid functional form. The loss of any of the above SrbA processing proteins results in a dysfunctional copy of SrbA and a subsequent loss of in vitro growth in hypoxia as well as attenuated virulence. Chromatin immunoprecipitation studies with the SrbA protein led to the identification of a second hypoxia regulator, SrbB. Although little is known about the processing of SrbB, this transcription factor has also shown to be a key player in virulence and the fungal hypoxia response. Similar to SrbA, a SrbB knockout mutant resulted in a loss of virulence, however, there was no heightened sensitivity towards antifungal drugs nor a complete loss of growth under hypoxic conditions (50% reduction in SrbB rather than 100% reduction in SrbA). In summary, both SrbA and SrbB have shown to be critical in the adaptation of A. fumigatus in the mammalian host.

Aspergillus fumigatus must acquire nutrients from its external environment to survive and flourish within its host. Many of the genes involved in such processes have been shown to impact virulence through experiments involving genetic mutation. Examples of nutrient uptake include that of metals, nitrogen, and macromolecules such as peptides.{{cite journal | vauthors = Dagenais TR, Keller NP | title = Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis | journal = Clinical Microbiology Reviews | volume = 22 | issue = 3 | pages = 447–65 | date = July 2009 | pmid = 19597008 | pmc = 2708386 | doi = 10.1128/CMR.00055-08 }}

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Iron is a necessary cofactor for many enzymes, and can act as a catalyst in the electron transport system. A. fumigatus has two mechanisms for the uptake of iron, reductive iron acquisition and siderophore-mediated.{{cite journal | vauthors = Haas H | title = Molecular genetics of fungal siderophore biosynthesis and uptake: the role of siderophores in iron uptake and storage | journal = Applied Microbiology and Biotechnology | volume = 62 | issue = 4 | pages = 316–30 | date = September 2003 | pmid = 12759789 | doi = 10.1007/s00253-003-1335-2 | s2cid = 10989925 }}{{cite journal | vauthors = Schrettl M, Bignell E, Kragl C, Joechl C, Rogers T, Arst HN, Haynes K, Haas H | display-authors = 6 | title = Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence | journal = The Journal of Experimental Medicine | volume = 200 | issue = 9 | pages = 1213–9 | date = November 2004 | pmid = 15504822 | pmc = 2211866 | doi = 10.1084/jem.20041242 }} Reductive iron acquisition includes conversion of iron from the ferric (Fe⁺³) to the ferrous (Fe⁺²) state and subsequent uptake via FtrA, an iron permease. Targeted mutation of the ftrA gene did not induce a decrease in virulence in the murine model of A. fumigatus invasion. In contrast, targeted mutation of sidA, the first gene in the siderophore biosynthesis pathway, proved siderophore-mediated iron uptake to be essential for virulence.{{cite journal | vauthors = Hissen AH, Wan AN, Warwas ML, Pinto LJ, Moore MM | title = The Aspergillus fumigatus siderophore biosynthetic gene sidA, encoding L-ornithine N5-oxygenase, is required for virulence | journal = Infection and Immunity | volume = 73 | issue = 9 | pages = 5493–503 | date = September 2005 | pmid = 16113265 | pmc = 1231119 | doi = 10.1128/IAI.73.9.5493-5503.2005 }} Mutation of the downstream siderophore biosynthesis genes sidC, sidD, sidF and sidG resulted in strains of A. fumigatus with similar decreases in virulence. These mechanisms of iron uptake appear to work in parallel and both are upregulated in response to iron starvation.

Aspergillus fumigatus can survive on a variety of different nitrogen sources, and the assimilation of nitrogen is of clinical importance, as it has been shown to affect virulence.{{cite journal | vauthors = Hensel M, Arst HN, Aufauvre-Brown A, Holden DW | title = The role of the Aspergillus fumigatus areA gene in invasive pulmonary aspergillosis | journal = Molecular & General Genetics | volume = 258 | issue = 5 | pages = 553–7 | date = June 1998 | pmid = 9669338 | doi = 10.1007/s004380050767 | s2cid = 27753283 }} Proteins involved in nitrogen assimilation are transcriptionally regulated by the AfareA gene in A. fumigatus. Targeted mutation of the afareA gene showed a decrease in onset of mortality in a mouse model of invasion. The Ras regulated protein RhbA has also been implicated in nitrogen assimilation. RhbA was found to be transcriptionally upregulated following contact of A. fumigatus with human endothelial cells, and strains with targeted mutation of the rhbA gene showed decreased growth on poor nitrogen sources and reduced virulence in vivo.{{cite journal | vauthors = Panepinto JC, Oliver BG, Amlung TW, Askew DS, Rhodes JC | title = Expression of the Aspergillus fumigatus rheb homologue, rhbA, is induced by nitrogen starvation | journal = Fungal Genetics and Biology | volume = 36 | issue = 3 | pages = 207–14 | date = August 2002 | pmid = 12135576 | doi = 10.1016/S1087-1845(02)00022-1 }}

The human lung contains large quantities of collagen and elastin, proteins that allow for tissue flexibility.{{cite journal | vauthors = Rosenbloom J | title = Elastin: relation of protein and gene structure to disease | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 51 | issue = 6 | pages = 605–23 | date = December 1984 | pmid = 6150137 }} Aspergillus fumigatus produces and secretes elastases, proteases that cleave elastin in order to break down these macromolecular polymers for uptake. A significant correlation between the amount of elastase production and tissue invasion was first discovered in 1984.{{cite journal | vauthors = Kothary MH, Chase T, Macmillan JD | title = Correlation of elastase production by some strains of Aspergillus fumigatus with ability to cause pulmonary invasive aspergillosis in mice | journal = Infection and Immunity | volume = 43 | issue = 1 | pages = 320–5 | date = January 1984 | pmid = 6360904 | pmc = 263429 | doi = 10.1128/IAI.43.1.320-325.1984}} Clinical isolates have also been found to have greater elastase activity than environmental strains of A. fumigatus.{{cite journal | vauthors = Blanco JL, Hontecillas R, Bouza E, Blanco I, Pelaez T, Muñoz P, Perez Molina J, Garcia ME | display-authors = 6 | title = Correlation between the elastase activity index and invasiveness of clinical isolates of Aspergillus fumigatus | journal = Journal of Clinical Microbiology | volume = 40 | issue = 5 | pages = 1811–3 | date = May 2002 | pmid = 11980964 | pmc = 130931 | doi = 10.1128/JCM.40.5.1811-1813.2002 }} A number of elastases have been characterized, including those from the serine protease, aspartic protease, and metalloprotease families.{{cite journal | vauthors = Reichard U, Büttner S, Eiffert H, Staib F, Rüchel R | title = Purification and characterisation of an extracellular serine proteinase from Aspergillus fumigatus and its detection in tissue | journal = Journal of Medical Microbiology | volume = 33 | issue = 4 | pages = 243–51 | date = December 1990 | pmid = 2258912 | doi = 10.1099/00222615-33-4-243 | doi-access = free }}{{cite journal | vauthors = Markaryan A, Morozova I, Yu H, Kolattukudy PE | title = Purification and characterization of an elastinolytic metalloprotease from Aspergillus fumigatus and immunoelectron microscopic evidence of secretion of this enzyme by the fungus invading the murine lung | journal = Infection and Immunity | volume = 62 | issue = 6 | pages = 2149–57 | date = June 1994 | pmid = 8188335 | pmc = 186491 | doi = 10.1128/IAI.62.6.2149-2157.1994}}{{cite journal | vauthors = Lee JD, Kolattukudy PE | title = Molecular cloning of the cDNA and gene for an elastinolytic aspartic proteinase from Aspergillus fumigatus and evidence of its secretion by the fungus during invasion of the host lung | journal = Infection and Immunity | volume = 63 | issue = 10 | pages = 3796–803 | date = October 1995 | pmid = 7558282 | pmc = 173533 | doi = 10.1128/IAI.63.10.3796-3803.1995}}{{cite journal | vauthors = Iadarola P, Lungarella G, Martorana PA, Viglio S, Guglielminetti M, Korzus E, Gorrini M, Cavarra E, Rossi A, Travis J, Luisetti M | display-authors = 6 | title = Lung injury and degradation of extracellular matrix components by Aspergillus fumigatus serine proteinase | journal = Experimental Lung Research | volume = 24 | issue = 3 | pages = 233–51 | year = 1998 | pmid = 9635248 | doi = 10.3109/01902149809041532 }} Yet, the large redundancy of these elastases has hindered the identification of specific effects on virulence.

A number of studies found that the unfolded protein response contributes to virulence of A. fumigatus.{{cite journal | vauthors = Feng X, Krishnan K, Richie DL, Aimanianda V, Hartl L, Grahl N, Powers-Fletcher MV, Zhang M, Fuller KK, Nierman WC, Lu LJ, Latgé JP, Woollett L, Newman SL, Cramer RA, Rhodes JC, Askew DS | display-authors = 6 | title = HacA-independent functions of the ER stress sensor IreA synergize with the canonical UPR to influence virulence traits in Aspergillus fumigatus | journal = PLOS Pathogens | volume = 7 | issue = 10 | pages = e1002330 | date = October 2011 | pmid = 22028661 | pmc = 3197630 | doi = 10.1371/journal.ppat.1002330 | doi-access = free }}

File:Secondary metabolite regulation by LaeA.jpg

The lifecycle of filamentous fungi including Aspergillus spp. consists of two phases: a hyphal growth phase and a reproductive (sporulation) phase. The switch between growth and reproductive phases of these fungi is regulated in part by the level of secondary metabolite production.{{cite journal | vauthors = Calvo AM, Wilson RA, Bok JW, Keller NP | title = Relationship between secondary metabolism and fungal development | journal = Microbiology and Molecular Biology Reviews | volume = 66 | issue = 3 | pages = 447–59, table of contents | date = September 2002 | pmid = 12208999 | pmc = 120793 | doi = 10.1128/MMBR.66.3.447-459.2002 }}{{cite journal | vauthors = Tao L, Yu JH | title = AbaA and WetA govern distinct stages of Aspergillus fumigatus development | journal = Microbiology | volume = 157 | issue = Pt 2 | pages = 313–26 | date = February 2011 | pmid = 20966095 | doi = 10.1099/mic.0.044271-0 | doi-access = free }} The secondary metabolites are believed to be produced to activate sporulation and pigments required for sporulation structures.{{cite journal | vauthors = Adams TH, Yu JH | title = Coordinate control of secondary metabolite production and asexual sporulation in Aspergillus nidulans | journal = Current Opinion in Microbiology | volume = 1 | issue = 6 | pages = 674–7 | date = December 1998 | pmid = 10066549 | doi = 10.1016/S1369-5274(98)80114-8 }} G protein signaling regulates secondary metabolite production.{{cite journal | vauthors = Brodhagen M, Keller NP | title = Signalling pathways connecting mycotoxin production and sporulation | journal = Molecular Plant Pathology | volume = 7 | issue = 4 | pages = 285–301 | date = July 2006 | pmid = 20507448 | doi = 10.1111/j.1364-3703.2006.00338.x | doi-access = free }} Genome sequencing has revealed 40 potential genes involved in secondary metabolite production including mycotoxins, which are produced at the time of sporulation.{{cite journal | vauthors = Nierman WC, Pain A, Anderson MJ, Wortman JR, Kim HS, Arroyo J, Berriman M, Abe K, Archer DB, Bermejo C, Bennett J, Bowyer P, Chen D, Collins M, Coulsen R, Davies R, Dyer PS, Farman M, Fedorova N, Fedorova N, Feldblyum TV, Fischer R, Fosker N, Fraser A, García JL, García MJ, Goble A, Goldman GH, Gomi K, Griffith-Jones S, Gwilliam R, Haas B, Haas H, Harris D, Horiuchi H, Huang J, Humphray S, Jiménez J, Keller N, Khouri H, Kitamoto K, Kobayashi T, Konzack S, Kulkarni R, Kumagai T, Lafon A, Lafton A, Latgé JP, Li W, Lord A, Lu C, Majoros WH, May GS, Miller BL, Mohamoud Y, Molina M, Monod M, Mouyna I, Mulligan S, Murphy L, O'Neil S, Paulsen I, Peñalva MA, Pertea M, Price C, Pritchard BL, Quail MA, Rabbinowitsch E, Rawlins N, Rajandream MA, Reichard U, Renauld H, Robson GD, Rodriguez de Córdoba S, Rodríguez-Peña JM, Ronning CM, Rutter S, Salzberg SL, Sanchez M, Sánchez-Ferrero JC, Saunders D, Seeger K, Squares R, Squares S, Takeuchi M, Tekaia F, Turner G, Vazquez de Aldana CR, Weidman J, White O, Woodward J, Yu JH, Fraser C, Galagan JE, Asai K, Machida M, Hall N, Barrell B, Denning DW | display-authors = 6 | title = Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus | journal = Nature | volume = 438 | issue = 7071 | pages = 1151–6 | date = December 2005 | pmid = 16372009 | doi = 10.1038/nature04332 | bibcode = 2005Natur.438.1151N | doi-access = free | hdl = 10261/71531 | hdl-access = free }}{{cite journal | vauthors = Trail F, Mahanti N, Linz J | title = Molecular biology of aflatoxin biosynthesis | journal = Microbiology | volume = 141 | issue = 4 | pages = 755–65 | date = April 1995 | pmid = 7773383 | doi = 10.1099/13500872-141-4-755 | doi-access = free }}

Gliotoxin is a mycotoxin capable of altering host defenses through immunosuppression. Neutrophils are the principal targets of gliotoxin.{{cite journal | vauthors = Spikes S, Xu R, Nguyen CK, Chamilos G, Kontoyiannis DP, Jacobson RH, Ejzykowicz DE, Chiang LY, Filler SG, May GS | display-authors = 6 | title = Gliotoxin production in Aspergillus fumigatus contributes to host-specific differences in virulence | journal = The Journal of Infectious Diseases | volume = 197 | issue = 3 | pages = 479–86 | date = February 2008 | pmid = 18199036 | doi = 10.1086/525044 | doi-access = free }}{{cite journal | vauthors = Bok JW, Chung D, Balajee SA, Marr KA, Andes D, Nielsen KF, Frisvad JC, Kirby KA, Keller NP | display-authors = 6 | title = GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus virulence | journal = Infection and Immunity | volume = 74 | issue = 12 | pages = 6761–8 | date = December 2006 | pmid = 17030582 | pmc = 1698057 | doi = 10.1128/IAI.00780-06 }} Gliotoxin interrupts the function of leukocytes by inhibiting migration and superoxide production and causes apoptosis in macrophages.{{cite journal | vauthors = Kamei K, Watanabe A | title = Aspergillus mycotoxins and their effect on the host | journal = Medical Mycology | volume = 43 | pages = S95-9 | date = May 2005 | issue = Suppl 1 | pmid = 16110799 | doi = 10.1080/13693780500051547 | doi-access = free }} Gliotoxin disrupts the proinflammatory response through inhibition of NF-κB.{{cite journal | vauthors = Gardiner DM, Waring P, Howlett BJ | title = The epipolythiodioxopiperazine (ETP) class of fungal toxins: distribution, mode of action, functions and biosynthesis | journal = Microbiology | volume = 151 | issue = Pt 4 | pages = 1021–1032 | date = April 2005 | pmid = 15817772 | doi = 10.1099/mic.0.27847-0 | doi-access = free }}

LaeA and GliZ are transcription factors known to regulate the production of gliotoxin. LaeA is a universal regulator of secondary metabolite production in Aspergillus spp. LaeA influences the expression of 9.5% of the A. fumigatus genome, including many secondary metabolite biosynthesis genes such as nonribosomal peptide synthetases.{{cite journal | vauthors = Perrin RM, Fedorova ND, Bok JW, Cramer RA, Wortman JR, Kim HS, Nierman WC, Keller NP | display-authors = 6 | title = Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA | journal = PLOS Pathogens | volume = 3 | issue = 4 | pages = e50 | date = April 2007 | pmid = 17432932 | pmc = 1851976 | doi = 10.1371/journal.ppat.0030050 | doi-access = free }} The production of numerous secondary metabolites, including gliotoxin, were impaired in an LaeA mutant (ΔlaeA) strain. The ΔlaeA mutant showed increased susceptibility to macrophage phagocytosis and decreased ability to kill neutrophils ex vivo. LaeA regulated toxins, besides gliotoxin, likely have a role in virulence since loss of gliotoxin production alone did not recapitulate the hypo-virulent ∆laeA pathotype.

Current noninvasive treatments used to combat fungal infections consist of a class of drugs known as azoles. Azole drugs such as voriconazole, itraconazole, and imidazole kill fungi by inhibiting the production of ergosterol—a critical element of fungal cell membranes. Mechanistically, these drugs act by inhibiting the fungal cytochrome p450 enzyme known as 14α-demethylase.{{cite journal | vauthors = Panackal AA, Bennett JE, Williamson PR | title = Treatment options in Invasive Aspergillosis | journal = Current Treatment Options in Infectious Diseases | volume = 6 | issue = 3 | pages = 309–325 | date = September 2014 | pmid = 25328449 | pmc = 4200583 | doi = 10.1007/s40506-014-0016-2 }} However, A. fumigatus resistance to azoles is increasing, potentially due to the use of low levels of azoles in agriculture.{{cite journal | vauthors = Berger S, El Chazli Y, Babu AF, Coste AT | title = Aspergillus fumigatus: A Consequence of Antifungal Use in Agriculture? | journal = Frontiers in Microbiology | volume = 8 | pages = 1024 | date = 2017-06-07 | pmid = 28638374 | pmc = 5461301 | doi = 10.3389/fmicb.2017.01024 | doi-access = free }}{{cite journal | vauthors = Bueid A, Howard SJ, Moore CB, Richardson MD, Harrison E, Bowyer P, Denning DW | title = Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009 | journal = The Journal of Antimicrobial Chemotherapy | volume = 65 | issue = 10 | pages = 2116–8 | date = October 2010 | pmid = 20729241 | doi = 10.1093/jac/dkq279 | doi-access = free }} The main mode of resistance is through mutations in the cyp51a gene.{{cite journal | vauthors = Nash A, Rhodes J | title = Simulations of CYP51A from Aspergillus fumigatus in a model bilayer provide insights into triazole drug resistance | journal = Medical Mycology | volume = 56 | issue = 3 | pages = 361–373 | date = April 2018 | pmid = 28992260 | doi = 10.1093/mmy/myx056 | pmc = 5895076 | doi-access = free }}{{cite journal | vauthors = Snelders E, Karawajczyk A, Schaftenaar G, Verweij PE, Melchers WJ | title = Azole resistance profile of amino acid changes in Aspergillus fumigatus CYP51A based on protein homology modeling | journal = Antimicrobial Agents and Chemotherapy | volume = 54 | issue = 6 | pages = 2425–30 | date = June 2010 | pmid = 20385860 | pmc = 2876375 | doi = 10.1128/AAC.01599-09 }} However, other modes of resistance have been observed accounting for almost 40% of resistance in clinical isolates.{{cite journal | vauthors = Rybak JM, Ge W, Wiederhold NP, Parker JE, Kelly SL, Rogers PD, Fortwendel JR | title = hmg1, Challenging the Paradigm of Clinical Triazole Resistance in Aspergillus fumigatus | journal = mBio | volume = 10 | issue = 2 | pages = e00437–19, /mbio/10/2/mBio.00437–19.atom | date = April 2019 | pmid = 30940706 | pmc = 6445940 | doi = 10.1128/mBio.00437-19 | veditors = Alspaugh JA }}{{cite journal | vauthors = Camps SM, Dutilh BE, Arendrup MC, Rijs AJ, Snelders E, Huynen MA, Verweij PE, Melchers WJ | display-authors = 6 | title = Discovery of a HapE mutation that causes azole resistance in Aspergillus fumigatus through whole genome sequencing and sexual crossing | journal = PLOS ONE | volume = 7 | issue = 11 | pages = e50034 | date = 2012-11-30 | pmid = 23226235 | pmc = 3511431 | doi = 10.1371/journal.pone.0050034 | bibcode = 2012PLoSO...750034C | doi-access = free }}{{cite journal | vauthors = Furukawa T, van Rhijn N, Fraczek M, Gsaller F, Davies E, Carr P, Gago S, Fortune-Grant R, Rahman S, Gilsenan JM, Houlder E, Kowalski CH, Raj S, Paul S, Cook P, Parker JE, Kelly S, Cramer RA, Latgé JP, Moye-Rowley S, Bignell E, Bowyer P, Bromley MJ | display-authors = 6 | title = The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus | journal = Nature Communications | volume = 11 | issue = 1 | pages = 427 | date = January 2020 | pmid = 31969561 | doi = 10.1038/s41467-019-14191-1 | doi-access = free | pmc = 7194077 | bibcode = 2020NatCo..11..427F }} Along with azoles, other anti-fungal drug classes do exist such as polyenes and echinocandins.{{citation needed|date=March 2022}}

Image:Aspergillus fumigatus 01.jpg

Image:Conidia phialoconidia of Aspergillus fumigatus PHIL 300 lores.jpg|Conidia phialoconidia of A. fumigatus

Image:070522-aspergillus 009.jpg|Colony in Petri dish

Image:Aspergillus fumigatus.jpg|A. fumigatus isolated from woodland soil

Image:10523 Aspergillus fumigatus.jpg|Slide of an infected turkey brain

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• 2012 US meningitis outbreak
• Allergic bronchopulmonary aspergillosis
• Aspergilloma
• Diseases of the honeybee
• Fumagillin
• RodA
• Galactosaminogalactan

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{{Reflist|32em}}

• [https://web.archive.org/web/20090901085906/http://www.scivee.tv/node/8254 Emergence of Azole Resistance in Aspergillus fumigatus and Spread of a Single Resistance Mechanism.] at SciVee
• [https://web.archive.org/web/20060615035930/http://www.aspergillustrust.org/ The Aspergillus Trust] A registered UK charity engaged in support of people with aspergillus disease worldwide and research into cures
• [http://www.aspergillus.man.ac.uk/ The Fungal Research Trust]
• Aspergillus info from [https://web.archive.org/web/20060420032238/http://doctorfungus.org/thefungi/Aspergillus_spp.htm DoctorFungus.org]

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Fumigatus

Category:Fungi described in 1863

Category:Fungal pathogens of humans

Category:Fungus species