Aspergillus fumigatus
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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.
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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref name="pmid16607012">Template:Cite journal</ref> Thus, the capability for sex is maintained, though little genetic variation is produced.
The fungus is capable of growth at Template:Convert (normal human body temperature), and can grow at temperatures up to Template:Convert, with conidia surviving at Template:Convert—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%.<ref name="pmid28203225">Template:Cite journal</ref> Several virulence factors have been postulated to explain this opportunistic behaviour.<ref name="pmid20974273">Template:Cite journal</ref>
When the fermentation broth of A. fumigatus was screened, a number of indolic alkaloids with antimitotic properties were discovered.<ref name=Cui>Template:Cite journal</ref> 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.<ref name=PMC126391>Template:Cite journal</ref>
Genome
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.<ref>Template:Cite journal</ref><ref name="pmid16372009"/><ref>Template:Cite journal</ref>
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.<ref name="pmid20618330">Template:Cite journal</ref> A. fumigatus primarily causes invasive infection in the lung and represents a major cause of morbidity and mortality in these individuals.<ref name="pmid17890370">Template:Cite journal</ref> Additionally, A. fumigatus can cause chronic pulmonary infections, allergic bronchopulmonary aspergillosis, or allergic disease in immunocompetent hosts.<ref name="pmid19403905">Template:Cite journal</ref>
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.<ref name="pmid19403905" /> A large portion of inhaled conidia are cleared by the mucociliary action of the respiratory epithelium.<ref name="pmid19403905" /> Due to the small size of conidia, many of them deposit in alveoli, where they interact with epithelial and innate effector cells.<ref name="pmid20618330" /><ref name="pmid19403905" /> Alveolar macrophages phagocytize and destroy conidia within their phagosomes.<ref name="pmid20618330" /><ref name="pmid19403905" /> Epithelial cells, specifically type II pneumocytes, also internalize conidia which traffic to the lysosome where ingested conidia are destroyed.<ref name="pmid20618330" /><ref name="pmid19403905" /><ref name="pmid17196036">Template:Cite journal</ref> 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.<ref name="pmid19403905"/> 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.<ref name="pmid20618330"/><ref name="pmid17890370"/><ref name="pmid19403905"/> Hyphae are too large for cell-mediated internalization, and thus neutrophil-mediated NADPH-oxidase-induced damage represents the dominant host defense against hyphae.<ref name="pmid20618330"/><ref name="pmid19403905"/> In addition to these cell-mediated mechanisms of elimination, antimicrobial peptides secreted by the airway epithelium contribute to host defense.<ref name="pmid20618330"/> 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<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
Invasion
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.<ref name="pmid20618330"/> Germination occurs both extracellularly or in type II pneumocyte endosomes containing conidia.<ref name="pmid20618330"/><ref name="pmid17196036"/> Following germination, filamentous hyphal growth results in epithelial penetration and subsequent penetration of the vascular endothelium.<ref name="pmid20618330"/><ref name="pmid17196036"/> The process of angioinvasion causes endothelial damage and induces a proinflammatory response, tissue factor expression and activation of the coagulation cascade.<ref name="pmid20618330"/> This results in intravascular thrombosis and localized tissue infarction, however, dissemination of hyphal fragments is usually limited.<ref name="pmid20618330"/><ref name="pmid17196036"/> Dissemination through the blood stream only occurs in severely immunocompromised individuals.<ref name="pmid17196036"/>
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.<ref name="pmid19462332">Template:Cite journal</ref><ref name="Grahl_2012">Template:Cite journal</ref><ref name="pmid20560863">Template:Cite journal</ref> 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.<ref name="Grahl_2012" /> 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.<ref name="Willger_2008">Template:Cite journal</ref> 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.<ref name="Chung_2014">Template:Cite journal</ref> 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.<ref name="pmid27303716">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="pmid23104569">Template:Cite journal</ref> 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.<ref name="Chung_2014"/> 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.<ref name="Chung_2014"/> 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).<ref name="Chung_2014"/><ref name="Willger_2008"/> 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.<ref name="pmid17890370"/><ref name="pmid19597008">Template:Cite journal</ref>
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.<ref name="pmid12759789">Template:Cite journal</ref><ref name="pmid15504822">Template:Cite journal</ref> 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.<ref name="pmid15504822"/><ref name="pmid16113265">Template:Cite journal</ref> Mutation of the downstream siderophore biosynthesis genes sidC, sidD, sidF and sidG resulted in strains of A. fumigatus with similar decreases in virulence.<ref name="pmid17845073" /> These mechanisms of iron uptake appear to work in parallel and both are upregulated in response to iron starvation.<ref name="pmid15504822"/>
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.<ref name="pmid19597008"/><ref name="pmid9669338">Template:Cite journal</ref> 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.<ref name="pmid9669338"/> 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.<ref name="pmid12135576">Template:Cite journal</ref>
Proteinases
The human lung contains large quantities of collagen and elastin, proteins that allow for tissue flexibility.<ref name="pmid6150137">Template:Cite journal</ref> 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.<ref name="pmid6360904">Template:Cite journal</ref> Clinical isolates have also been found to have greater elastase activity than environmental strains of A. fumigatus.<ref name="pmid11980964">Template:Cite journal</ref> A number of elastases have been characterized, including those from the serine protease, aspartic protease, and metalloprotease families.<ref name="pmid2258912">Template:Cite journal</ref><ref name="pmid8188335">Template:Cite journal</ref><ref name="pmid7558282">Template:Cite journal</ref><ref name="pmid9635248">Template:Cite journal</ref> Yet, the large redundancy of these elastases has hindered the identification of specific effects on virulence.<ref name="pmid17890370"/><ref name="pmid19597008"/>
Unfolded protein response
A number of studies found that the unfolded protein response contributes to virulence of A. fumigatus.<ref>Template:Cite journal</ref>
Secondary metabolism
Secondary metabolites in fungal development
The lifecycle of filamentous fungi including Aspergillus spp. consists of two phases: a hyphas 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.<ref name="pmid12208999">Template:Cite journal</ref><ref name="pmid20966095">Template:Cite journal</ref> The secondary metabolites are believed to be produced to activate sporulation and pigments required for sporulation structures.<ref name="pmid10066549">Template:Cite journal</ref> G protein signaling regulates secondary metabolite production.<ref name="pmid20507448">Template:Cite journal</ref> Genome sequencing has revealed 40 potential genes involved in secondary metabolite production including mycotoxins, which are produced at the time of sporulation.<ref name="pmid16372009">Template:Cite journal</ref><ref name="pmid7773383">Template:Cite journal</ref>
Gliotoxin
Gliotoxin is a mycotoxin capable of altering host defenses through immunosuppression. Neutrophils are the principal targets of gliotoxin.<ref name="pmid18199036">Template:Cite journal</ref><ref name="pmid17030582">Template:Cite journal</ref> Gliotoxin interrupts the function of leukocytes by inhibiting migration and superoxide production and causes apoptosis in macrophages.<ref name="pmid16110799">Template:Cite journal</ref> Gliotoxin disrupts the proinflammatory response through inhibition of NF-κB.<ref name="pmid15817772">Template:Cite journal</ref>
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.<ref name="pmid15075281"/> LaeA influences the expression of 9.5% of the A. fumigatus genome, including many secondary metabolite biosynthesis genes such as nonribosomal peptide synthetases.<ref name="pmid17432932">Template:Cite journal</ref> The production of numerous secondary metabolites, including gliotoxin, were impaired in an LaeA mutant (ΔlaeA) strain.<ref name="pmid17432932"/> The ΔlaeA mutant showed increased susceptibility to macrophage phagocytosis and decreased ability to kill neutrophils ex vivo.<ref name="pmid17030582"/> 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.<ref name="pmid17432932"/>
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.<ref>Template:Cite journal</ref> However, A. fumigatus resistance to azoles is increasing, potentially due to the use of low levels of azoles in agriculture.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The main mode of resistance is through mutations in the cyp51a gene.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> However, other modes of resistance have been observed accounting for almost 40% of resistance in clinical isolates.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Along with azoles, other anti-fungal drug classes do exist such as polyenes and echinocandins.Template:Citation needed
Viral symbiont
A. fumigatus has long been known to harbor the virus A. fumigatus Polymycovirus-1 (AfuPmV-1M). A 2025 study says that the virus appears to strengthen the fungus. Giving antiviral drugs to infected mice increased their survival rate. (Though a 2020 study found that anitviral drugs reduced their survival rate.)<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>
Gallery
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Conidia phialoconidia of A. fumigatus
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Colony in Petri dish
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A. fumigatus isolated from woodland soil
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Slide of an infected turkey brain
See also
- Allergic bronchopulmonary aspergillosis
- Aspergilloma
- Fumagillin
- Galactosaminogalactan
- List of diseases of the honeybee
- New England Compounding Center meningitis outbreak (2012)
- RodA
References
External links
- Emergence of Azole Resistance in Aspergillus fumigatus and Spread of a Single Resistance Mechanism. at SciVee
- The Aspergillus Trust A registered UK charity engaged in support of people with aspergillus disease worldwide and research into cures
- The Fungal Research Trust
- Aspergillus info from DoctorFungus.org