Aspergillus fumigatus

Last updated

Aspergillus fumigatus
Aspergillus.jpg
Scientific classification OOjs UI icon edit-ltr.svg
Domain: Eukaryota
Kingdom: Fungi
Division: Ascomycota
Class: Eurotiomycetes
Order: Eurotiales
Family: Aspergillaceae
Genus: Aspergillus
Species:
A. fumigatus
Binomial name
Aspergillus fumigatus
Fresenius 1863
Synonyms

Neosartorya fumigata
O'Gorman, Fuller & Dyer 2008

Aspergillus fumigatus is a species of fungus in the genus Aspergillus , and is one of the most common Aspergillus species to cause disease in individuals with an immunodeficiency.

Contents

Aspergillus fumigatus, a saprotroph widespread in nature, is typically found in soil and decaying organic matter, such as compost heaps, where it plays an essential role in carbon and nitrogen recycling. [1] Colonies of the fungus produce from conidiophores; thousands of minute grey-green conidia (2–3 μm) which readily become airborne. For many years, A. fumigatus was thought to only reproduce asexually, as neither mating nor meiosis had ever been observed. In 2008, A. fumigatus was shown to possess a fully functional sexual reproductive cycle, 145 years after its original description by Fresenius. [2] Although A. fumigatus occurs in areas with widely different climates and environments, it displays low genetic variation and a lack of population genetic differentiation on a global scale. [3] Thus, the capability for sex is maintained, though little genetic variation is produced.

The fungus is capable of growth at 37 °C or 99 °F (normal human body temperature), and can grow at temperatures up to 50 °C or 122 °F, with conidia surviving at 70 °C or 158 °F—conditions it regularly encounters in self-heating compost heaps. Its spores are ubiquitous in the atmosphere, and everybody inhales an estimated several hundred spores each day; typically, these are quickly eliminated by the immune system in healthy individuals. In immunocompromised individuals, such as organ transplant recipients and people with AIDS or leukemia, the fungus is more likely to become pathogenic, over-running the host's weakened defenses and causing a range of diseases generally termed aspergillosis. Due to the recent increase in the use of immunosuppressants to treat human illnesses, it is estimated that A. fumigatus may be responsible for over 600,000 deaths annually with a mortality rate between 25 and 90%. [4] Several virulence factors have been postulated to explain this opportunistic behaviour. [5]

When the fermentation broth of A. fumigatus was screened, a number of indolic alkaloids with antimitotic properties were discovered. [6] The compounds of interest have been of a class known as tryprostatins, with spirotryprostatin B being of special interest as an anticancer drug.

Aspergillus fumigatus grown on certain building materials can produce genotoxic and cytotoxic mycotoxins, such as gliotoxin. [7]

Genome

Aspergillus fumigatus has a stable haploid genome of 29.4 million base pairs. The genome sequences of three Aspergillus speciesAspergillus fumigatus, Aspergillus nidulans , and Aspergillus oryzae were published in Nature in December 2005. [8] [9] [10]

Pathogenesis

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. [11] A. fumigatus primarily causes invasive infection in the lung and represents a major cause of morbidity and mortality in these individuals. [12] Additionally, A. fumigatus can cause chronic pulmonary infections, allergic bronchopulmonary aspergillosis, or allergic disease in immunocompetent hosts. [13]

Innate immune response

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. [13] A large portion of inhaled conidia are cleared by the mucociliary action of the respiratory epithelium. [13] Due to the small size of conidia, many of them deposit in alveoli, where they interact with epithelial and innate effector cells. [11] [13] Alveolar macrophages phagocytize and destroy conidia within their phagosomes. [11] [13] Epithelial cells, specifically type II pneumocytes, also internalize conidia which traffic to the lysosome where ingested conidia are destroyed. [11] [13] [14] 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. [13] 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. [11] [12] [13] Hyphae are too large for cell-mediated internalization, and thus neutrophil-mediated NADPH-oxidase induced damage represents the dominant host defense against hyphae. [11] [13] In addition to these cell-mediated mechanisms of elimination, antimicrobial peptides secreted by the airway epithelium contribute to host defense. [11] 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 [15] [16]

Invasion

Schematic of invasive Aspergillus infection: Hyphae germinate either within an epithelial cell or within the alveoli. Hyphae extend through the epithelial cells, eventually invading and traversing endothelial cells of the vasculature. In rare cases, hyphal fragments break off and disseminate through the blood stream. Aspergillus fumigatus Invasive Disease Mechanism Diagram.jpg
Schematic of invasive Aspergillus infection: Hyphae germinate either within an epithelial cell or within the alveoli. Hyphae extend through the epithelial cells, eventually invading and traversing endothelial cells of the vasculature. In rare cases, hyphal fragments break off and disseminate through the blood stream.

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. [11] Germination occurs both extracellularly or in type II pneumocyte endosomes containing conidia. [11] [14] Following germination, filamentous hyphal growth results in epithelial penetration and subsequent penetration of the vascular endothelium. [11] [14] The process of angioinvasion causes endothelial damage and induces a proinflammatory response, tissue factor expression and activation of the coagulation cascade. [11] This results in intravascular thrombosis and localized tissue infarction, however, dissemination of hyphal fragments is usually limited. [11] [14] Dissemination through the blood stream only occurs in severely immunocompromised individuals. [14]

Hypoxia response

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. [17] [18] [19] 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. [18] 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. [20] 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. [21] 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. [22] [23] [24] 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. [21] 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. [21] 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). [21] [20] In summary, both SrbA and SrbB have shown to be critical in the adaptation of A. fumigatus in the mammalian host.

Nutrient acquisition

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. [12] [25]

Proposed Siderophore Biosynthetic Pathway of Aspergillus fumigatus: sidA catalyzes the first step in the biosynthesis of both the extracellular siderophore triacetylfusarinine C and intracellular ferricrocin Journal.ppat.0030128.g001.png
Proposed Siderophore Biosynthetic Pathway of Aspergillus fumigatus: sidA catalyzes the first step in the biosynthesis of both the extracellular siderophore triacetylfusarinine C and intracellular ferricrocin

Iron acquisition

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. [27] [28] 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. [28] [29] Mutation of the downstream siderophore biosynthesis genes sidC, sidD, sidF and sidG resulted in strains of A. fumigatus with similar decreases in virulence. [26] These mechanisms of iron uptake appear to work in parallel and both are upregulated in response to iron starvation. [28]

Nitrogen assimilation

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. [25] [30] 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. [30] 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 . [31]

Proteinases

The human lung contains large quantities of collagen and elastin, proteins that allow for tissue flexibility. [32] 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. [33] Clinical isolates have also been found to have greater elastase activity than environmental strains of A. fumigatus. [34] A number of elastases have been characterized, including those from the serine protease, aspartic protease, and metalloprotease families. [35] [36] [37] [38] Yet, the large redundancy of these elastases has hindered the identification of specific effects on virulence. [12] [25]

Unfolded protein response

A number of studies found that the unfolded protein response contributes to virulence of A. fumigatus. [39]

Secondary metabolism

Secondary metabolites in fungal development

The transcription factor LaeA regulates the expression of several genes involved in secondary metabolite production in Aspergillus spp. Secondary metabolite regulation by LaeA.jpg
The transcription factor LaeA regulates the expression of several genes involved in secondary metabolite production in Aspergillus spp.

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. [41] [42] The secondary metabolites are believed to be produced to activate sporulation and pigments required for sporulation structures. [43] G protein signaling regulates secondary metabolite production. [44] Genome sequencing has revealed 40 potential genes involved in secondary metabolite production including mycotoxins, which are produced at the time of sporulation. [9] [45]

Gliotoxin

Gliotoxin is a mycotoxin capable of altering host defenses through immunosuppression. Neutrophils are the principal targets of gliotoxin. [46] [47] Gliotoxin interrupts the function of leukocytes by inhibiting migration and superoxide production and causes apoptosis in macrophages. [48] Gliotoxin disrupts the proinflammatory response through inhibition of NF-κB. [49]

Transcriptional regulation of gliotoxin

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. [40] LaeA influences the expression of 9.5% of the A. fumigatus genome, including many secondary metabolite biosynthesis genes such as nonribosomal peptide synthetases. [50] The production of numerous secondary metabolites, including gliotoxin, were impaired in an LaeA mutant (ΔlaeA) strain. [50] The ΔlaeA mutant showed increased susceptibility to macrophage phagocytosis and decreased ability to kill neutrophils ex vivo . [47] 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. [50]

Current treatments to combat A. fumigatus infections

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. [51] However, A. fumigatus resistance to azoles is increasing, potentially due to the use of low levels of azoles in agriculture. [52] [53] The main mode of resistance is through mutations in the cyp51a gene. [54] [55] However, other modes of resistance have been observed accounting for almost 40% of resistance in clinical isolates. [56] [57] [58] Along with azoles, other anti-fungal drug classes do exist such as polyenes and echinocandins.[ citation needed ]

See also

Related Research Articles

<i>Candida albicans</i> Species of fungus

Candida albicans is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is usually a commensal organism, but it can become pathogenic in immunocompromised individuals under a variety of conditions. It is one of the few species of the genus Candida that cause the human infection candidiasis, which results from an overgrowth of the fungus. Candidiasis is, for example, often observed in HIV-infected patients. C. albicans is the most common fungal species isolated from biofilms either formed on (permanent) implanted medical devices or on human tissue. C. albicans, C. tropicalis, C. parapsilosis, and C. glabrata are together responsible for 50–90% of all cases of candidiasis in humans. A mortality rate of 40% has been reported for patients with systemic candidiasis due to C. albicans. By one estimate, invasive candidiasis contracted in a hospital causes 2,800 to 11,200 deaths yearly in the US. Nevertheless, these numbers may not truly reflect the true extent of damage this organism causes, given new studies indicating that C. albicans can cross the blood–brain barrier in mice.

<span class="mw-page-title-main">Antifungal</span> Pharmaceutical fungicide or fungistatic used to treat and prevent mycosis

An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. Such drugs are usually obtained by a doctor's prescription, but a few are available over the counter (OTC). The evolution of antifungal resistance is a growing threat to health globally.

<i>Aspergillus flavus</i> Species of fungus

Aspergillus flavus is a saprotrophic and pathogenic fungus with a cosmopolitan distribution. It is best known for its colonization of cereal grains, legumes, and tree nuts. Postharvest rot typically develops during harvest, storage, and/or transit. Its specific name flavus derives from the Latin meaning yellow, a reference to the frequently observed colour of the spores. A. flavus infections can occur while hosts are still in the field (preharvest), but often show no symptoms (dormancy) until postharvest storage or transport. In addition to causing preharvest and postharvest infections, many strains produce significant quantities of toxic compounds known as mycotoxins, which, when consumed, are toxic to mammals. A. flavus is also an opportunistic human and animal pathogen, causing aspergillosis in immunocompromised individuals.

<i>Aspergillus</i> Genus of fungi

Aspergillus is a genus consisting of several hundred mould species found in various climates worldwide.

<i>Pseudomonas aeruginosa</i> Species of bacterium

Pseudomonas aeruginosa is a common encapsulated, Gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, P. aeruginosa is a multidrug resistant pathogen recognized for its ubiquity, its intrinsically advanced antibiotic resistance mechanisms, and its association with serious illnesses – hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes.

<i>Nakaseomyces glabratus</i> Species of fungus

Nakaseomyces glabratus is a species of haploid yeast of the genus Nakaseomyces, previously known as Candida glabrata. Despite the fact that no sexual life cycle has been documented for this species, N. glabratus strains of both mating types are commonly found. C. glabrata is generally a commensal of human mucosal tissues, but in today's era of wider human immunodeficiency from various causes, N. glabratus is often the second or third most common cause of candidiasis as an opportunistic pathogen. Infections caused by N. glabratus can affect the urogenital tract or even cause systemic infections by entrance of the fungal cells in the bloodstream (Candidemia), especially prevalent in immunocompromised patients.

Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:

<span class="mw-page-title-main">Aspergillosis</span> Medical condition

Aspergillosis is a fungal infection of usually the lungs, caused by the genus Aspergillus, a common mould that is breathed in frequently from the air, but does not usually affect most people. It generally occurs in people with lung diseases such as asthma, cystic fibrosis or tuberculosis, or those who are immunocompromized such as those who have had a stem cell or organ transplant or those who take medications such as steroids and some cancer treatments which suppress the immune system. Rarely, it can affect skin.

<span class="mw-page-title-main">Gliotoxin</span> Chemical compound

Gliotoxin is a sulfur-containing mycotoxin that belongs to a class of naturally occurring 2,5-diketopiperazines produced by several species of fungi, especially those of marine origin. It is the most prominent member of the epipolythiopiperazines, a large class of natural products featuring a diketopiperazine with di- or polysulfide linkage. These highly bioactive compounds have been the subject of numerous studies aimed at new therapeutics. Gliotoxin was originally isolated from Gliocladium fimbriatum, and was named accordingly. It is an epipolythiodioxopiperazine metabolite that is one of the most abundantly produced metabolites in human invasive Aspergillosis (IA).

<i>Burkholderia cenocepacia</i> Species of bacterium

Burkholderia cenocepacia is a Gram-negative, rod-shaped bacterium that is commonly found in soil and water environments and may also be associated with plants and animals, particularly as a human pathogen. It is one of over 20 species in the Burkholderia cepacia complex (Bcc) and is notable due to its virulence factors and inherent antibiotic resistance that render it a prominent opportunistic pathogen responsible for life-threatening, nosocomial infections in immunocompromised patients, such as those with cystic fibrosis or chronic granulomatous disease. The quorum sensing systems CepIR and CciIR regulate the formation of biofilms and the expression of virulence factors such as siderophores and proteases. Burkholderia cenocepacia may also cause disease in plants, such as in onions and bananas. Additionally, some strains serve as plant growth-promoting rhizobacteria.

<i>Aspergillus terreus</i> Species of fungus

Aspergillus terreus, also known as Aspergillus terrestris, is a fungus (mold) found worldwide in soil. Although thought to be strictly asexual until recently, A. terreus is now known to be capable of sexual reproduction. This saprotrophic fungus is prevalent in warmer climates such as tropical and subtropical regions. Aside from being located in soil, A. terreus has also been found in habitats such as decomposing vegetation and dust. A. terreus is commonly used in industry to produce important organic acids, such as itaconic acid and cis-aconitic acid, as well as enzymes, like xylanase. It was also the initial source for the drug mevinolin (lovastatin), a drug for lowering serum cholesterol.

<i>Setosphaeria rostrata</i> Pathogenic fungus

Setosphaeria rostrata is a heat tolerant fungus with an asexual reproductive form (anamorph) known as Exserohilum rostratum. This fungus is a common plant pathogen, causing leaf spots as well as crown rot and root rot in grasses. It is also found in soils and on textiles in subtropical and tropical regions. Exserohilum rostratum is one of the 35 Exserohilum species implicated uncommonly as opportunistic pathogens of humans where it is an etiologic agent of sinusitis, keratitis, skin lesions and an often fatal meningoencephalitis. Infections caused by this species are most often seen in regions with hot climates like Israel, India and the southern USA.

<span class="mw-page-title-main">Sterol 14-demethylase</span> Class of enzymes

In enzymology, a sterol 14-demethylase (EC 1.14.13.70) is an enzyme of the Cytochrome P450 (CYP) superfamily. It is any member of the CYP51 family. It catalyzes a chemical reaction such as:

Pathogenic fungi are fungi that cause disease in humans or other organisms. Although fungi are eukaryotic, many pathogenic fungi are microorganisms. Approximately 300 fungi are known to be pathogenic to humans; their study is called "medical mycology". Fungal infections kill more people than either tuberculosis or malaria—about 2 million people per year.

<span class="mw-page-title-main">Chronic pulmonary aspergillosis</span> Fungal infection

Chronic pulmonary aspergillosis is a long-term fungal infection caused by members of the genus Aspergillus—most commonly Aspergillusfumigatus. The term describes several disease presentations with considerable overlap, ranging from an aspergilloma—a clump of Aspergillus mold in the lungs—through to a subacute, invasive form known as chronic necrotizing pulmonary aspergillosis which affects people whose immune system is weakened. Many people affected by chronic pulmonary aspergillosis have an underlying lung disease, most commonly tuberculosis, allergic bronchopulmonary aspergillosis, asthma, or lung cancer.

In biology, a pathogen, in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ.

Scedosporiosis is the general name for any mycosis - i.e., fungal infection - caused by a fungus from the genus Scedosporium. Current population-based studies suggest Scedosporium prolificans and Scedosporium apiospermum to be among the most common infecting agents from the genus, although infections caused by other members thereof are not unheard of. The latter is an asexual form (anamorph) of another fungus, Pseudallescheria boydii. The former is a “black yeast”, currently not characterized as well, although both of them have been described as saprophytes.

Aspergillus calidoustus is a species of fungus in the section Ustus, which grows at 37 °C and exhibits high minimal inhibitory concentrations to azoles. It is considered an agent of opportunistic infection.

<span class="mw-page-title-main">Velvet complex</span> Fungus protein

Velvet complex is a group of proteins found in fungi and especially molds that are important in reproduction and production of secondary metabolites including penicillin. The core members of the complex include VeA, LaeA, and VelB. Other proteins including VelC and VosA sometimes function in the complex. The proteins were first characterized in Aspergillus nidulans.

Aspergillus giganteus is a species of fungus in the genus Aspergillus that grows as a mold. It was first described in 1901 by Wehmer, and is one of six Aspergillus species from the Clavati section of the subgenus Fumigati. Its closest taxonomic relatives are Aspergillus rhizopodus and Aspergillus longivescia.

References

  1. Fang W, Latgé JP (August 2018). "Microbe Profile: Aspergillus fumigatus: a saprotrophic and opportunistic fungal pathogen". Microbiology. 164 (8): 1009–1011. doi:10.1099/mic.0.000651. PMC   6152418 . PMID   30066670.
  2. O'Gorman CM, Fuller H, Dyer PS (January 2009). "Discovery of a sexual cycle in the opportunistic fungal pathogen Aspergillus fumigatus". Nature. 457 (7228): 471–4. Bibcode:2009Natur.457..471O. doi:10.1038/nature07528. PMID   19043401. S2CID   4371721.
  3. Rydholm C, Szakacs G, Lutzoni F (April 2006). "Low genetic variation and no detectable population structure in aspergillus fumigatus compared to closely related Neosartorya species". Eukaryotic Cell. 5 (4): 650–7. doi:10.1128/EC.5.4.650-657.2006. PMC   1459663 . PMID   16607012.
  4. Dhingra S, Cramer RA (2017). "Regulation of Sterol Biosynthesis in the Human Fungal Pathogen Aspergillus fumigatus: Opportunities for Therapeutic Development". Frontiers in Microbiology. 8: 92. doi: 10.3389/fmicb.2017.00092 . PMC   5285346 . PMID   28203225.
  5. Abad A, Fernández-Molina JV, Bikandi J, Ramírez A, Margareto J, Sendino J, et al. (December 2010). "What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis" (PDF). Revista Iberoamericana de Micologia. 27 (4): 155–82. doi:10.1016/j.riam.2010.10.003. PMID   20974273.
  6. Cui CB, Kakeya H, Osada H (August 1996). "Spirotryprostatin B, a novel mammalian cell cycle inhibitor produced by Aspergillus fumigatus". The Journal of Antibiotics. 49 (8): 832–5. doi: 10.7164/antibiotics.49.832 . PMID   8823522.
  7. Nieminen SM, Kärki R, Auriola S, Toivola M, Laatsch H, Laatikainen R, et al. (October 2002). "Isolation and identification of Aspergillus fumigatus mycotoxins on growth medium and some building materials". Applied and Environmental Microbiology. 68 (10): 4871–5. Bibcode:2002ApEnM..68.4871N. doi:10.1128/aem.68.10.4871-4875.2002. PMC   126391 . PMID   12324333.
  8. Galagan JE, Calvo SE, Cuomo C, Ma LJ, Wortman JR, Batzoglou S, et al. (December 2005). "Sequencing of Aspergillus nidulans and comparative analysis with A. fumigatus and A. oryzae". Nature. 438 (7071): 1105–15. Bibcode:2005Natur.438.1105G. doi: 10.1038/nature04341 . PMID   16372000.
  9. 1 2 Nierman WC, Pain A, Anderson MJ, Wortman JR, Kim HS, Arroyo J, et al. (December 2005). "Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus". Nature. 438 (7071): 1151–6. Bibcode:2005Natur.438.1151N. doi: 10.1038/nature04332 . hdl: 10261/71531 . PMID   16372009.
  10. Machida M, Asai K, Sano M, Tanaka T, Kumagai T, Terai G, et al. (December 2005). "Genome sequencing and analysis of Aspergillus oryzae". Nature. 438 (7071): 1157–61. Bibcode:2005Natur.438.1157M. doi: 10.1038/nature04300 . PMID   16372010.
  11. 1 2 3 4 5 6 7 8 9 10 11 12 13 Ben-Ami R, Lewis RE, Kontoyiannis DP (August 2010). "Enemy of the (immunosuppressed) state: an update on the pathogenesis of Aspergillus fumigatus infection". British Journal of Haematology. 150 (4): 406–17. doi: 10.1111/j.1365-2141.2010.08283.x . PMID   20618330. S2CID   28216163.
  12. 1 2 3 4 Hohl TM, Feldmesser M (November 2007). "Aspergillus fumigatus: principles of pathogenesis and host defense". Eukaryotic Cell. 6 (11): 1953–63. doi:10.1128/EC.00274-07. PMC   2168400 . PMID   17890370.
  13. 1 2 3 4 5 6 7 8 9 Segal BH (April 2009). "Aspergillosis". The New England Journal of Medicine. 360 (18): 1870–84. doi:10.1056/NEJMra0808853. PMID   19403905.
  14. 1 2 3 4 5 6 Filler SG, Sheppard DC (December 2006). "Fungal invasion of normally non-phagocytic host cells". PLOS Pathogens. 2 (12): e129. doi: 10.1371/journal.ppat.0020129 . PMC   1757199 . PMID   17196036.
  15. Karnam A, Bonam SR, Rambabu N, Wong SS, Aimanianda V, Bayry J (November 16, 2021). "Wnt-β-Catenin Signaling in Human Dendritic Cells Mediates Regulatory T-Cell Responses to Fungi via the PD-L1 Pathway". mBio. 12 (6): e0282421. doi: 10.1128/mBio.02824-21 . PMC   8593687 . PMID   34781737.
  16. 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 (December 5, 2017). "Aspergillus fumigatus Cell Wall α-(1,3)-Glucan Stimulates Regulatory T-Cell Polarization by Inducing PD-L1 Expression on Human Dendritic Cells". J Infect Dis. 216 (10): 1281–1294. doi: 10.1093/infdis/jix469 . PMID   28968869.
  17. Grahl N, Cramer RA (February 2010). "Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi?". Medical Mycology. 48 (1): 1–15. doi:10.3109/13693780902947342. PMC   2898717 . PMID   19462332.
  18. 1 2 Grahl N, Shepardson KM, Chung D, Cramer RA (May 2012). "Hypoxia and fungal pathogenesis: to air or not to air?". Eukaryotic Cell. 11 (5): 560–70. doi:10.1128/EC.00031-12. PMC   3346435 . PMID   22447924.
  19. Wezensky SJ, Cramer RA (April 2011). "Implications of hypoxic microenvironments during invasive aspergillosis". Medical Mycology. 49 (Suppl 1): S120–4. doi:10.3109/13693786.2010.495139. PMC   2951492 . PMID   20560863.
  20. 1 2 Willger SD, Puttikamonkul S, Kim KH, Burritt JB, Grahl N, Metzler LJ, Barbuch R, Bard M, Lawrence CB, Cramer RA (November 2008). "A sterol-regulatory element binding protein is required for cell polarity, hypoxia adaptation, azole drug resistance, and virulence in Aspergillus fumigatus". PLOS Pathogens. 4 (11): e1000200. doi: 10.1371/journal.ppat.1000200 . PMC   2572145 . PMID   18989462.
  21. 1 2 3 4 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 (November 2014). "ChIP-seq and in vivo transcriptome analyses of the Aspergillus fumigatus SREBP SrbA reveals a new regulator of the fungal hypoxia response and virulence". PLOS Pathogens. 10 (11): e1004487. doi: 10.1371/journal.ppat.1004487 . PMC   4223079 . PMID   25375670.
  22. Dhingra S, Kowalski CH, Thammahong A, Beattie SR, Bultman KM, Cramer RA (2016). "RbdB, a Rhomboid Protease Critical for SREBP Activation and Virulence in Aspergillus fumigatus". mSphere. 1 (2). doi:10.1128/mSphere.00035-16. PMC   4863583 . PMID   27303716.
  23. Bat-Ochir C, Kwak JY, Koh SK, Jeon MH, Chung D, Lee YW, Chae SK (May 2016). "The signal peptide peptidase SppA is involved in sterol regulatory element-binding protein cleavage and hypoxia adaptation in Aspergillus nidulans". Molecular Microbiology. 100 (4): 635–55. doi: 10.1111/mmi.13341 . PMID   26822492.
  24. Willger SD, Cornish EJ, Chung D, Fleming BA, Lehmann MM, Puttikamonkul S, Cramer RA (December 2012). "Dsc orthologs are required for hypoxia adaptation, triazole drug responses, and fungal virulence in Aspergillus fumigatus". Eukaryotic Cell. 11 (12): 1557–67. doi:10.1128/EC.00252-12. PMC   3536281 . PMID   23104569.
  25. 1 2 3 Dagenais TR, Keller NP (July 2009). "Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis". Clinical Microbiology Reviews. 22 (3): 447–65. doi:10.1128/CMR.00055-08. PMC   2708386 . PMID   19597008.
  26. 1 2 Schrettl M, Bignell E, Kragl C, Sabiha Y, Loss O, Eisendle M, et al. (September 2007). "Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection". PLOS Pathogens. 3 (9): 1195–207. doi: 10.1371/journal.ppat.0030128 . PMC   1971116 . PMID   17845073.
  27. Haas H (September 2003). "Molecular genetics of fungal siderophore biosynthesis and uptake: the role of siderophores in iron uptake and storage". Applied Microbiology and Biotechnology. 62 (4): 316–30. doi:10.1007/s00253-003-1335-2. PMID   12759789. S2CID   10989925.
  28. 1 2 3 Schrettl M, Bignell E, Kragl C, Joechl C, Rogers T, Arst HN, et al. (November 2004). "Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence". The Journal of Experimental Medicine. 200 (9): 1213–9. doi:10.1084/jem.20041242. PMC   2211866 . PMID   15504822.
  29. Hissen AH, Wan AN, Warwas ML, Pinto LJ, Moore MM (September 2005). "The Aspergillus fumigatus siderophore biosynthetic gene sidA, encoding L-ornithine N5-oxygenase, is required for virulence". Infection and Immunity. 73 (9): 5493–503. doi:10.1128/IAI.73.9.5493-5503.2005. PMC   1231119 . PMID   16113265.
  30. 1 2 Hensel M, Arst HN, Aufauvre-Brown A, Holden DW (June 1998). "The role of the Aspergillus fumigatus areA gene in invasive pulmonary aspergillosis". Molecular & General Genetics. 258 (5): 553–7. doi:10.1007/s004380050767. PMID   9669338. S2CID   27753283.
  31. Panepinto JC, Oliver BG, Amlung TW, Askew DS, Rhodes JC (August 2002). "Expression of the Aspergillus fumigatus rheb homologue, rhbA, is induced by nitrogen starvation". Fungal Genetics and Biology. 36 (3): 207–14. doi:10.1016/S1087-1845(02)00022-1. PMID   12135576.
  32. Rosenbloom J (December 1984). "Elastin: relation of protein and gene structure to disease". Laboratory Investigation; A Journal of Technical Methods and Pathology. 51 (6): 605–23. PMID   6150137.
  33. Kothary MH, Chase T, Macmillan JD (January 1984). "Correlation of elastase production by some strains of Aspergillus fumigatus with ability to cause pulmonary invasive aspergillosis in mice". Infection and Immunity. 43 (1): 320–5. doi:10.1128/IAI.43.1.320-325.1984. PMC   263429 . PMID   6360904.
  34. Blanco JL, Hontecillas R, Bouza E, Blanco I, Pelaez T, Muñoz P, et al. (May 2002). "Correlation between the elastase activity index and invasiveness of clinical isolates of Aspergillus fumigatus". Journal of Clinical Microbiology. 40 (5): 1811–3. doi:10.1128/JCM.40.5.1811-1813.2002. PMC   130931 . PMID   11980964.
  35. Reichard U, Büttner S, Eiffert H, Staib F, Rüchel R (December 1990). "Purification and characterisation of an extracellular serine proteinase from Aspergillus fumigatus and its detection in tissue". Journal of Medical Microbiology. 33 (4): 243–51. doi: 10.1099/00222615-33-4-243 . PMID   2258912.
  36. Markaryan A, Morozova I, Yu H, Kolattukudy PE (June 1994). "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". Infection and Immunity. 62 (6): 2149–57. doi:10.1128/IAI.62.6.2149-2157.1994. PMC   186491 . PMID   8188335.
  37. Lee JD, Kolattukudy PE (October 1995). "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". Infection and Immunity. 63 (10): 3796–803. doi:10.1128/IAI.63.10.3796-3803.1995. PMC   173533 . PMID   7558282.
  38. Iadarola P, Lungarella G, Martorana PA, Viglio S, Guglielminetti M, Korzus E, et al. (1998). "Lung injury and degradation of extracellular matrix components by Aspergillus fumigatus serine proteinase". Experimental Lung Research. 24 (3): 233–51. doi:10.3109/01902149809041532. PMID   9635248.
  39. Feng X, Krishnan K, Richie DL, Aimanianda V, Hartl L, Grahl N, et al. (October 2011). "HacA-independent functions of the ER stress sensor IreA synergize with the canonical UPR to influence virulence traits in Aspergillus fumigatus". PLOS Pathogens. 7 (10): e1002330. doi: 10.1371/journal.ppat.1002330 . PMC   3197630 . PMID   22028661.
  40. 1 2 Bok JW, Keller NP (April 2004). "LaeA, a regulator of secondary metabolism in Aspergillus spp". Eukaryotic Cell. 3 (2): 527–35. doi:10.1128/EC.3.2.527-535.2004. PMC   387652 . PMID   15075281.
  41. Calvo AM, Wilson RA, Bok JW, Keller NP (September 2002). "Relationship between secondary metabolism and fungal development". Microbiology and Molecular Biology Reviews. 66 (3): 447–59, table of contents. doi:10.1128/MMBR.66.3.447-459.2002. PMC   120793 . PMID   12208999.
  42. Tao L, Yu JH (February 2011). "AbaA and WetA govern distinct stages of Aspergillus fumigatus development". Microbiology. 157 (Pt 2): 313–26. doi: 10.1099/mic.0.044271-0 . PMID   20966095.
  43. Adams TH, Yu JH (December 1998). "Coordinate control of secondary metabolite production and asexual sporulation in Aspergillus nidulans". Current Opinion in Microbiology. 1 (6): 674–7. doi:10.1016/S1369-5274(98)80114-8. PMID   10066549.
  44. Brodhagen M, Keller NP (July 2006). "Signalling pathways connecting mycotoxin production and sporulation". Molecular Plant Pathology. 7 (4): 285–301. doi: 10.1111/j.1364-3703.2006.00338.x . PMID   20507448.
  45. Trail F, Mahanti N, Linz J (April 1995). "Molecular biology of aflatoxin biosynthesis". Microbiology. 141 (4): 755–65. doi: 10.1099/13500872-141-4-755 . PMID   7773383.
  46. Spikes S, Xu R, Nguyen CK, Chamilos G, Kontoyiannis DP, Jacobson RH, et al. (February 2008). "Gliotoxin production in Aspergillus fumigatus contributes to host-specific differences in virulence". The Journal of Infectious Diseases. 197 (3): 479–86. doi: 10.1086/525044 . PMID   18199036.
  47. 1 2 Bok JW, Chung D, Balajee SA, Marr KA, Andes D, Nielsen KF, et al. (December 2006). "GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus virulence". Infection and Immunity. 74 (12): 6761–8. doi:10.1128/IAI.00780-06. PMC   1698057 . PMID   17030582.
  48. Kamei K, Watanabe A (May 2005). "Aspergillus mycotoxins and their effect on the host". Medical Mycology. 43 (Suppl 1): S95-9. doi: 10.1080/13693780500051547 . PMID   16110799.
  49. Gardiner DM, Waring P, Howlett BJ (April 2005). "The epipolythiodioxopiperazine (ETP) class of fungal toxins: distribution, mode of action, functions and biosynthesis". Microbiology. 151 (Pt 4): 1021–1032. doi: 10.1099/mic.0.27847-0 . PMID   15817772.
  50. 1 2 3 Perrin RM, Fedorova ND, Bok JW, Cramer RA, Wortman JR, Kim HS, et al. (April 2007). "Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA". PLOS Pathogens. 3 (4): e50. doi: 10.1371/journal.ppat.0030050 . PMC   1851976 . PMID   17432932.
  51. Panackal AA, Bennett JE, Williamson PR (September 2014). "Treatment options in Invasive Aspergillosis". Current Treatment Options in Infectious Diseases. 6 (3): 309–325. doi:10.1007/s40506-014-0016-2. PMC   4200583 . PMID   25328449.
  52. Berger S, El Chazli Y, Babu AF, Coste AT (2017-06-07). "Aspergillus fumigatus: A Consequence of Antifungal Use in Agriculture?". Frontiers in Microbiology. 8: 1024. doi: 10.3389/fmicb.2017.01024 . PMC   5461301 . PMID   28638374.
  53. Bueid A, Howard SJ, Moore CB, Richardson MD, Harrison E, Bowyer P, Denning DW (October 2010). "Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009". The Journal of Antimicrobial Chemotherapy. 65 (10): 2116–8. doi: 10.1093/jac/dkq279 . PMID   20729241.
  54. Nash A, Rhodes J (April 2018). "Simulations of CYP51A from Aspergillus fumigatus in a model bilayer provide insights into triazole drug resistance". Medical Mycology. 56 (3): 361–373. doi: 10.1093/mmy/myx056 . PMC   5895076 . PMID   28992260.
  55. Snelders E, Karawajczyk A, Schaftenaar G, Verweij PE, Melchers WJ (June 2010). "Azole resistance profile of amino acid changes in Aspergillus fumigatus CYP51A based on protein homology modeling". Antimicrobial Agents and Chemotherapy. 54 (6): 2425–30. doi:10.1128/AAC.01599-09. PMC   2876375 . PMID   20385860.
  56. Rybak JM, Ge W, Wiederhold NP, Parker JE, Kelly SL, Rogers PD, Fortwendel JR (April 2019). Alspaugh JA (ed.). "hmg1, Challenging the Paradigm of Clinical Triazole Resistance in Aspergillus fumigatus". mBio. 10 (2): e00437–19, /mbio/10/2/mBio.00437–19.atom. doi:10.1128/mBio.00437-19. PMC   6445940 . PMID   30940706.
  57. Camps SM, Dutilh BE, Arendrup MC, Rijs AJ, Snelders E, Huynen MA, et al. (2012-11-30). "Discovery of a HapE mutation that causes azole resistance in Aspergillus fumigatus through whole genome sequencing and sexual crossing". PLOS ONE. 7 (11): e50034. Bibcode:2012PLoSO...750034C. doi: 10.1371/journal.pone.0050034 . PMC   3511431 . PMID   23226235.
  58. Furukawa T, van Rhijn N, Fraczek M, Gsaller F, Davies E, Carr P, et al. (January 2020). "The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus". Nature Communications. 11 (1): 427. Bibcode:2020NatCo..11..427F. doi: 10.1038/s41467-019-14191-1 . PMC   7194077 . PMID   31969561.