Aspergillus fumigatus
Encyclopedia
Aspergillus fumigatus is a fungus
of the genus Aspergillus
, and is one of the most common Aspergillus species to cause disease in individuals with an immunodeficiency
.
A. 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) that 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, however, A. fumigatus was shown to possess a fully functional sexual reproductive cycle, 145 years after its original description by Fresenius.
The fungus is capable of growth at 37 °C (99 °F) (normal human body temperature
), and can grow at temperatures up to 50 °C (122 °F), with conidia surviving at 70 °C (158 °F)—conditions it regularly encounters in self-heating compost heaps. Its spores are ubiquitous in the atmosphere, and it is estimated that everybody inhales 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
.
When the fermentation broth of A. fumigatus was screened, a number of indolic
alkaloid
s 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.
A. fumigatus grown on certain building materials can produce genotoxic
and cytotoxic mycotoxin
s, such as gliotoxin
.
s. The genome sequences of three Aspergillus species—Aspergillus fumigatus, Aspergillus nidulans
, and Aspergillus oryzae
—were published in the journal Nature
in December 2005.
s and chemokine
s 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.
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 immunocomprimised individuals.
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+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 sideophore biosynthesis pathway, proved sideophore-mediated iron uptake to be essential for virulence. Mutation of the downstream sideophore 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.
sources, and the assimilation
of nitrogen is of clinical importance as it has been shown to affect 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. 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
.
and elastin
, proteins that allow for tissue flexibility. Aspergillus fumigatus produces and secretes elastases, protease
s that cleave elastin in order to breakdown 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.
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.
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
of the genus Aspergillus
Aspergillus
Aspergillus is a genus consisting of several hundred mold species found in various climates worldwide. Aspergillus was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli...
, and is one of the most common Aspergillus species to cause disease in individuals with an immunodeficiency
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
.
A. 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
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
and nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
recycling. Colonies of the fungus produce from conidiophores thousands of minute grey-green conidia (2–3 μm) that 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, however, A. fumigatus was shown to possess a fully functional sexual reproductive cycle, 145 years after its original description by Fresenius.
The fungus is capable of growth at 37 °C (99 °F) (normal human body temperature
Normal human body temperature
Normal human body temperature, also known as normothermia or euthermia, is a concept that depends upon the place in the body at which the measurement is made, and the time of day and level of activity of the person...
), and can grow at temperatures up to 50 °C (122 °F), with conidia surviving at 70 °C (158 °F)—conditions it regularly encounters in self-heating compost heaps. Its spores are ubiquitous in the atmosphere, and it is estimated that everybody inhales several hundred spores each day; typically these are quickly eliminated by the immune system in healthy individuals. In immunocompromised
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
individuals, such as organ transplant recipients and people with AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
or leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
, the fungus is more likely to become pathogenic, over-running the host's weakened defenses and causing a range of diseases generally termed aspergillosis
Aspergillosis
Aspergillosis is the name given to a wide variety of diseases caused by fungi of the genus Aspergillus. The most common forms are allergic bronchopulmonary aspergillosis, pulmonary aspergilloma and invasive aspergillosis. Most humans inhale Aspergillus spores every day...
.
When the fermentation broth of A. fumigatus was screened, a number of indolic
Indole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...
alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
s with antimitotic
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
properties were discovered. The compounds of interest have been of a class known as tryprostatins, with spirotryprostatin B
Spirotryprostatin B
Spirotryprostatin B is an indolic alkaloid found in the Aspergillus fumigatus fungus. Spirotryprostatin B and several other indolic alkaloids have been found to have anti-mitotic properties, and as such they have become of great interest as anti-cancer drugs...
being of special interest as an anticancer drug.
A. fumigatus grown on certain building materials can produce genotoxic
Genotoxic
In genetics, genotoxicity describes a deleterious action on a cell's genetic material affecting its integrity. This includes both certain chemical compounds and certain types of radiation....
and cytotoxic mycotoxin
Mycotoxin
A mycotoxin is a toxic secondary metabolite produced by organisms of the fungus kingdom, commonly known as molds. The term ‘mycotoxin’ is usually reserved for the toxic chemical products produced by fungi that readily colonize crops...
s, such as gliotoxin
Gliotoxin
Gliotoxin is a sulfur-containing mycotoxin produced by several species of fungi, some of which are pathogens of humans such as Aspergillus, and also by species of Trichoderma, and Penicillium...
.
Genome
A. fumigatus has a stable haploid genome of 29.4 million base pairBase pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
s. The genome sequences of three Aspergillus species—Aspergillus fumigatus, Aspergillus nidulans
Aspergillus nidulans
Aspergillus nidulans is one of many species of filamentous fungi in the phylum Ascomycota...
, and Aspergillus oryzae
Aspergillus oryzae
Aspergillus oryzae is a filamentous fungus . It is used in Chinese and Japanese cuisine to ferment soybeans. It is also used to saccharify rice, other grains, and potatoes in the making of alcoholic beverages such as huangjiu, sake, and shōchū...
—were published in the journal Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...
in December 2005.
Pathogenesis
A. 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 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. A large portion of inhaled conidia are cleared by the mucociliary action of the respiratory epithelium. Due to the small size of conidia, many conidia 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. First line immune cells also serve to recruit neutrophils and other inflammatory cells through release of cytokineCytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s and chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
s induced by ligation of specific fungal motifs to pathogen recognition receptors
Pattern recognition receptor
Pattern recognition receptors are a primitive part of the immune system. They are proteins expressed by cells of the innate immune system to identify pathogen-associated molecular patterns , which are associated with microbial pathogens or cellular stress, as well as damage-associated molecular...
. 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.
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. Germination occurs both extracellularly or in type II pneumocyteType II pneumocyte
Type II pneumocytes also called great alveolar cells or septal cells are granular and roughly cuboidal in shape. Type II pneumocytes are typically found at the alveolar-septal junction...
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
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
cascade. This results in intravascular thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
and localized tissue infarction
Infarction
In medicine, infarction refers to tissue death that is caused by a local lack of oxygen due to obstruction of the tissue's blood supply. The resulting lesion is referred to as an infarct.-Causes:...
, however, dissemination of hyphal fragments is usually limited. Dissemination through the blood stream only occurs in severely immunocomprimised individuals.
Nutrient Acquisition
A. fumigatus must acquire nutrients from its external environment in order 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.Iron Acquisition
Iron is a necessary cofactorCofactor
Cofactor may refer to any of the following:* Cofactor , the signed minor of a matrix* Minor , an alternative name for the determinant of a smaller matrix than that which it describes...
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
Siderophore
Siderophores are small, high-affinity iron chelating compounds secreted by grasses and microorganisms such as bacteria and fungi...
-mediated. Reductive iron acquisition includes conversion of iron from the ferric
Ferric
Ferric refers to iron-containing materials or compounds. In chemistry the term is reserved for iron with an oxidation number of +3, also denoted iron or Fe3+. On the other hand, ferrous refers to iron with oxidation number of +2, denoted iron or Fe2+...
(Fe+3) to the ferrous
Ferrous
Ferrous , in chemistry, indicates a divalent iron compound , as opposed to ferric, which indicates a trivalent iron compound ....
(Fe+2) state and subsequent uptake via FtrA, an iron permease
Permease
The permeases are membrane transport proteins, a class of multipass transmembrane proteins that facilitate the diffusion of a specific molecule in or out of the cell by passive transport...
. 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 sideophore biosynthesis pathway, proved sideophore-mediated iron uptake to be essential for virulence. Mutation of the downstream sideophore 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.
Nitrogen assimilation
A. fumigatus can survive on a variety of different nitrogenNitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
sources, and the assimilation
Assimilation
Assimilation may refer to:*Assimilation , a linguistic process by which a sound becomes similar to an adjacent sound...
of nitrogen is of clinical importance as it has been shown to affect 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. The Ras
Ras
Ras is the name given to a family of related proteins found inside cells, including human cells. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells...
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
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
.
Proteinases
The human lung contains large quantities of collagenCollagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
and elastin
Elastin
Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...
, proteins that allow for tissue flexibility. Aspergillus fumigatus produces and secretes elastases, protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s that cleave elastin in order to breakdown 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
Serine protease
Serine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site.They are found ubiquitously in both eukaryotes and prokaryotes...
, aspartic protease, and metalloprotease families. Yet, the large redundancy of these elastases has hindered the identification of specific effects on virulence.
Secondary metabolites in fungal development
The life cycle 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. It is believed the secondary metabolites are 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. LaeA influences the expression of 9.5% of the A. fumigatus genome, including many secondary metabolite biosynthesis genes such as nonribosomal peptide synthetases (NRPSs). The production of numerous secondary metabolites, including gliotoxin, were impaired in an LaeA mutant (ΔlaeA) strain. The ΔlaeA mutant showed increased susceptibility to macrophageMacrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
phagocytosis and decreased ability to kill neutrophils ex vivo
Ex vivo
Ex vivo means that which takes place outside an organism. In science, ex vivo refers to experimentation or measurements done in or on tissue in an artificial environment outside the organism with the minimum alteration of natural conditions...
. 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.
See also
- Diseases of the honeybeeDiseases of the honeybee- Varroa mites :Varroa destructor and Varroa jacobsoni are parasitic mites that feed off the bodily fluids of adult, pupal and larval bees.Varroa mites can be seen with the naked eye as a small red or brown spot on the bee's thorax....
- AspergillosisAspergillosisAspergillosis is the name given to a wide variety of diseases caused by fungi of the genus Aspergillus. The most common forms are allergic bronchopulmonary aspergillosis, pulmonary aspergilloma and invasive aspergillosis. Most humans inhale Aspergillus spores every day...
- AspergillomaAspergillomaAn aspergilloma, also known as a mycetoma or fungus ball, is a clump of fungus which exists in a body cavity such as the lung. It is associated with the Aspergillus species, but Zygomycota and Fusarium may also form similar structures....
- Allergic bronchopulmonary aspergillosisAllergic bronchopulmonary aspergillosisIn medicine, allergic bronchopulmonary aspergillosis is a condition characterised by an exaggerated response of the immune system to the fungus Aspergillus . It occurs most often in patients with asthma or cystic fibrosis...
External links
- Emergence of Azole Resistance in Aspergillus fumigatus and Spread of a Single Resistance Mechanism. at SciVeeSciVeeSciVee is a science video sharing website where researchers can upload, view and share science video clips and connect them to scientific literature, posters and slides...
- The Aspergillus Trust A registered UK charity engaged in support of sufferers of aspergillus disease worldwide and research into cures
- The Fungal Research Trust
- Aspergillus info from DoctorFungus.org