Aspergillus fumigatus

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. 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. 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. Thus, the capability for sex is maintained, though little genetic variation is produced.

The fungus is capable of growth at (normal human body temperature), and can grow at temperatures up to , with conidia surviving at —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%. Several virulence factors have been postulated to explain this opportunistic behaviour.

When the fermentation broth of A. fumigatus was screened, a number of indolic alkaloids with antimitotic properties were discovered. 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.

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.

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

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. 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.

Invasion

thumb|right|300px|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. 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. 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. 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. 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.

thumb|left|300px|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. Reductive iron acquisition includes conversion of iron from the ferric (Fe<sup>+3</sup>) to the ferrous (Fe<sup>+2</sup>) 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. Mutation of the downstream siderophore biosynthesis genes sidC, sidD, sidF and sidG resulted in strains of A. fumigatus with similar decreases in virulence. 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.

Proteinases

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

Secondary metabolism

Secondary metabolites in fungal development

thumb|right|300px|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 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. The secondary metabolites are believed to be produced to activate sporulation and pigments required for sporulation structures. G protein signaling regulates secondary metabolite production. Genome sequencing has revealed 40 potential genes involved in secondary metabolite production including mycotoxins, which are produced at the time of sporulation.

Gliotoxin

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

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. The production of numerous secondary metabolites, including gliotoxin, were impaired in an LaeA mutant (ΔlaeA) strain. However, A. fumigatus resistance to azoles is increasing, potentially due to the use of low levels of azoles in agriculture. The main mode of resistance is through mutations in the cyp51a gene. However, other modes of resistance have been observed accounting for almost 40% of resistance in clinical isolates. Along with azoles, other anti-fungal drug classes do exist such as polyenes and echinocandins.

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.)

Gallery

File:Aspergillus fumigatus 01.jpg

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

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

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

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

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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