Aspergillus fumigatus is a species of fungus in the genusAspergillus, and is one of the most commonAspergillus species to cause disease in individuals with animmunodeficiency.
Aspergillus fumigatus, asaprotroph widespread in nature, is typically found in soil and decaying organic matter, such ascompost heaps, where it plays an essential role incarbon andnitrogen recycling.[1] Colonies of the fungus produce fromconidiophores; thousands of minute grey-greenconidia (2–3 μm) which readily become airborne. For many years,A. fumigatus was thought to only reproduce asexually, as neither mating normeiosis 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] AlthoughA. 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 (normalhuman 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. Inimmunocompromised individuals, such as organ transplant recipients and people with AIDS orleukemia, the fungus is more likely to becomepathogenic, over-running the host's weakened defenses and causing a range of diseases generally termedaspergillosis. 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] Severalvirulence factors have been postulated to explain thisopportunistic behaviour.[5]
When the fermentation broth ofA. fumigatus was screened, a number ofindolicalkaloids withantimitotic properties were discovered.[6] The compounds of interest have been of a class known as tryprostatins, withspirotryprostatin B being of special interest as an anticancer drug.
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]
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 toA. 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 inalveoli, where they interact with epithelial and innate effector cells.[11][13]Alveolar macrophages phagocytize and destroy conidia within theirphagosomes.[11][13] Epithelial cells, specifically type II pneumocytes, also internalize conidia which traffic to thelysosome where ingested conidia are destroyed.[11][13][14] First line immune cells also serve to recruitneutrophils and other inflammatory cells through release ofcytokines andchemokines induced by ligation of specific fungal motifs topathogen recognition receptors.[13] Neutrophils are essential for aspergillosis resistance, as demonstrated in neutropenic individuals, and are capable of sequestering both conidia andhyphae through distinct, non-phagocytic mechanisms.[11][12][13] Hyphae are too large for cell-mediated internalization, and thus neutrophil-mediatedNADPH-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 ofdendritic cells byWnt-β-Catenin signaling pathway to inducePD-L1 and to promoteregulatory T cell responses[15][16]
Schematic of invasiveAspergillus 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.[11][14]
Immunosuppressed individuals are susceptible to invasiveA. 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 intype 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 thecoagulation cascade.[11] This results in intravascularthrombosis and localized tissueinfarction, however, dissemination of hyphal fragments is usually limited.[11][14] Dissemination through the blood stream only occurs in severely immunocompromised individuals.[14]
As is common with tumor cells and other pathogens, the invasive hyphae ofA. 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 inperfusion, the passaging of fluids to organs. InA. 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 whichA. 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 ofA. 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 forA. 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 ofA. 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.[12][25]
Proposed Siderophore Biosynthetic Pathway ofAspergillus fumigatus: sidA catalyzes the first step in the biosynthesis of both the extracellular siderophore triacetylfusarinine C and intracellular ferricrocin[26]
Iron is a necessarycofactor for many enzymes, and can act as acatalyst in the electron transport system.A. fumigatus has two mechanisms for the uptake of iron, reductive iron acquisition andsiderophore-mediated.[27][28] Reductive iron acquisition includes conversion of iron from theferric (Fe+3) to theferrous (Fe+2) state and subsequent uptake via FtrA, an ironpermease. Targeted mutation of the ftrA gene did not induce a decrease in virulence in themurine model ofA. 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 ofA. 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]
Aspergillus fumigatus can survive on a variety of differentnitrogen sources, and theassimilation 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 inA. fumigatus. Targeted mutation of the afareA gene showed a decrease in onset of mortality in a mouse model of invasion.[30] TheRas regulated protein RhbA has also been implicated in nitrogen assimilation. RhbA was found to be transcriptionally upregulated following contact ofA. fumigatus with humanendothelial cells, and strains with targeted mutation of therhbAgene showed decreased growth on poor nitrogen sources and reduced virulencein vivo.[31]
The human lung contains large quantities ofcollagen andelastin, 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 ofA. fumigatus.[34] A number of elastases have been characterized, including those from theserine protease,aspartic protease, andmetalloprotease families.[35][36][37][38] Yet, the large redundancy of these elastases has hindered the identification of specific effects on virulence.[12][25]
The transcription factor LaeA regulates the expression of several genes involved in secondary metabolite production inAspergillus spp.[40]
The lifecycle of filamentous fungi includingAspergillus spp. consists of two phases: ahyphas 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] Thesecondary 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 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 ofNF-κB.[49]
LaeA and GliZ are transcription factors known to regulate the production of gliotoxin. LaeA is a universal regulator of secondary metabolite production inAspergillus spp.[40] LaeA influences the expression of 9.5% of theA. fumigatus genome, including many secondary metabolite biosynthesis genes such asnonribosomal 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 tomacrophage phagocytosis and decreased ability to kill neutrophilsex 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 combatA. fumigatus infections
Current noninvasive treatments used to combat fungal infections consist of a class of drugs known as azoles.Azole drugs such asvoriconazole,itraconazole, andimidazole kill fungi by inhibiting the production ofergosterol—a critical element of fungal cell membranes. Mechanistically, these drugs act by inhibiting the fungalcytochrome p450 enzyme known as14α-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 thecyp51a 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 aspolyenes andechinocandins.[citation needed]
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.)[59][60]
^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.PMID12759789.S2CID10989925.
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^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.PMID12135576.
^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.PMID6150137.
^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.PMID10066549.
