Tolypocladium inflatum

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Tolypocladium inflatum
Scientific classification OOjs UI icon edit-ltr.svg
Domain: Eukaryota
Kingdom: Fungi
Division: Ascomycota
Class: Sordariomycetes
Order: Hypocreales
Family: Ophiocordycipitaceae
Genus: Tolypocladium
T. inflatum
Binomial name
Tolypocladium inflatum
W. Gams (1971)
Synonyms [1] [2] [3] [4]

Pachybasium niveumO. Rostr. (1916)
Tolypocladium niveum(O. Rostr.) Bissett (1983)
Beauveria nivea(O. Rostr.) Arx (1986)
Cordyceps subsessilisPetch (1937)
Elaphocordyceps subsessilis(Petch) G.H. Sung, J.M. Sung & Spatafora (2007)


Tolypocladium inflatum is an ascomycete fungus originally isolated from a Norwegian soil sample that, under certain conditions, produces the immunosuppressant drug ciclosporin. [5] In its sexual stage (teleomorph) it is a parasite on scarab beetles. It forms a small, compound ascocarp that arises from the cadaver of its host beetle. In its asexual stage (anamorph) it is a white mold that grows on soil. It is much more commonly found in its asexual stage and this is the stage that was originally given the name Tolypocladium inflatum. [5]


In 1969, a soil sample containing microfungi from Norway, found by Hans Peter Frey. [6] was brought to Switzerland [5] from which a fungus misidentified as Trichoderma polysporum was isolated. [7] In 1971 the Austrian mycologist, Walter Gams, re-identified the isolate as a previously unknown microfungus affiliated with the order Hypocreales. [8] He erected the genus Tolypocladium to accommodate the isolate which he named T. inflatum Gams. [8] The taxon is characterized by swollen phialides, sparingly branched conidiophores, and small, unicellular conidia borne in slimy heads. [8] Canadian mycologist John Bissett re-examined the strain in 1983, finding it to match the species Pachybasium niveum, a fungus described prior to the work of Gams. According to the rules of publication priority for botanical nomenclature, Bissett proposed the combination Tolypocladium niveum. [8] However due to the economic importance of the fungus to the pharmaceutical industry and the fact that the incorrect name had already become well-entrenched, a proposal to formally conserve the name T. inflatum against earlier names was made and accepted, establishing the correct name of the mold that produces ciclosporin as Tolypocladium inflatum.

Growth and morphology

Tolypocladium inflatum occurs most commonly in soil or leaf litter, particularly at high latitudes in cold soils. [8] The species is characterized by spherically swollen phialides that are terminated with narrow necks bearing subglobose conidia. [8] T. inflatum is highly tolerant of lead and has been found to dominate the mycota of lead-contaminated soils. [9] A study conducted by Baath et al. found that 35% of the fungal isolates recovered from lead-laden soil were T. inflatum. [9]

In 1996, Kathie Hodge of Cornell University and colleagues determined that the mold T. inflatum was the asexual state of what was then known as Cordyceps subsessilis. [10] Cordyceps subsessilis was later moved to the genus Elaphocordyceps. However, under the ICN's 2011 "one fungus, one name" principle, fungi can not have different names for their anamorphic and teleomorphic stages if they are found to be the same species so Elaphocordyceps subsessilis was made a synonym of Tolypocladium inflatum. [1] [11]

The genome of the T. inflatum strain/isolate NRRL 8044 (ATCC 34921) was sequenced and published in 2013 by Bushley and colleagues. [12] This was the same strain from which the ciclosporin was first isolated.

Metabolite production

Tolypocladium inflatum is similar to other fungi in the order Hypocreales in generating a variety of biologically active secondary metabolites. [13] Two significant groups of metabolites are produced from T. inflatum: ciclosporins and efrapeptins. [10] Ciclosporin exhibits insecticidal and antifungal properties [10] and is a key immunosuppressant drug used to prevent the rejection of transplanted organs. [13] Ciclosporin A also has the potential use in the treatment of autoimmune diseases. [10] The genome of filamentous T. inflatum contains a 12-gene cluster associated with a repetitive element. [13] [14] Efrapeptins are mitochondrial and prokaryotic ATPase inhibitors that also have insecticidal and antifungal properties. [10] Little is known about the role of these metabolites in the ecology of the fungus. [10] In 2011, Linn and co-workers studied crude extracts of T. inflatum and found that the fungus produced six new secondary metabolites and four other chlamydosporol derivatives. [15]


Although Tolypocladium inflatum is chiefly as a soil fungus [13] its sexual state has been encountered as a pathogen of insects, [10] specifically beetle larvae. [13] Hodge and co-workers suggested that the fungus may have originated as an insect pathogen but evolved over time survive asexually as a facultative soil saprobe. [10] Although T. inflatum has not been shown to affect nematodes, researchers Samson and Soares hypothesized that the Tolypocladium species may have a nematode alternate host. [10] Tolypocladium inflatum has also shown to produce substances that inhibit the in vitro growth of a number of fungal species. [16] Some suggest that T. inflatum may also have the ability to inhibit certain fungal plant pathogens from colonizing their hosts. [16] For example, T. inflatum had a small but significant effect on inhibiting mycorrhiza formation. [16] Furthermore, secondary metabolites isolated from the crude extract of T. inflatum have shown modest cytotoxicity against eight human tumour cell lines including A549 (human lung adenocarcinoma), A375 (human malignant melanoma), and MCF-7 (human breast cancer). [15]

Medical uses

Tolypocladium inflatum has long been of interest in biotechnology due to its production of a relatively non-cytotoxic, natural 11 amino acid [17] cyclic peptide [18] named Ciclosporin A. [13] Ciclosporin is an immunosuppressant drug used in the management of autoimmune diseases and the prevention of rejection in organ transplantation. [5] Ciclosporin A works by targeting and binding with human ciclophilin A. [13] This ciclosporine-ciclophilin binding inhibits calcineurin and effectively inhibits the human immune system. [13] Without calcineurin, the activity of nuclear factor of activated T-cells and transcription regulators of IL-2 in T-lymphocytes is blocked. [13] Ciclosporin A considerably alters the nuclear morphology of in vitro human peripheral blood mononuclear leukocytes from ovoid to a radially splayed lobulated structure. [17] The expression levels of alanine racemase affects the level of cyclosporine production by T. inflatum. [18] Ciclosporin A was first introduced in medical use in the 1970s after an organ transplant to reduce graft rejection. [19] This use was based on cyclosporin’s ability to interfere with lymphokine biosynthesis. [19] Ciclosporin A also has anti-inflammatory, antifungal, and antiparasitic abilities. It has been recommended for autoimmune diseases as well as potential treatment for rheumatoid arthritis, type I diabetes, and HIV-1. [18] Despite its use in medicine, cyclosporine A exhibits significant nephrotoxicity, cardiotoxicity, and hepathotoxicity. [20] Drugs containing T. inflatum-produced cyclosporin A are a major product of the pharmaceutical company, Novartis. [5]

Related Research Articles

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

Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, eczema, and in organ transplants to prevent rejection. It is also used as eye drops for keratoconjunctivitis sicca.

<span class="mw-page-title-main">Entomopathogenic fungus</span> Fungus that can act as a parasite of insects

An entomopathogenic fungus is a fungus that can kill or seriously disable insects.

<i>Trichoderma harzianum</i> Species of fungus

Trichoderma harzianum is a fungus that is also used as a fungicide. It is used for foliar application, seed treatment and soil treatment for suppression of fungal pathogens causing various fungal plant diseases. Commercial biotechnological products such as 3Tac have been useful for treatment of Botrytis, Fusarium and Penicillium sp. It is also used for manufacturing enzymes.

<i>Trichoderma</i> Genus of fungi

Trichoderma is a genus of fungi in the family Hypocreaceae that is present in all soils, where they are the most prevalent culturable fungi. Many species in this genus can be characterized as opportunistic avirulent plant symbionts. This refers to the ability of several Trichoderma species to form mutualistic endophytic relationships with several plant species. The genomes of several Trichoderma specieshave been sequenced and are publicly available from the JGI.

Hyphomycetes are a form classification of fungi, part of what has often been referred to as fungi imperfecti, Deuteromycota, or anamorphic fungi. Hyphomycetes lack closed fruit bodies, and are often referred to as moulds. Most hyphomycetes are now assigned to the Ascomycota, on the basis of genetic connections made by life-cycle studies or by phylogenetic analysis of DNA sequences; many remain unassigned phylogenetically.

<i>Beauveria</i> Genus of fungi

Beauveria is a genus of asexually-reproducing fungi allied with the ascomycete family Cordycipitaceae. Its several species are typically insect pathogens. The sexual states (teleomorphs) of Beauveria species, where known, are species of Cordyceps.

<i>Ophiocordyceps unilateralis</i> Species of fungus

Ophiocordyceps unilateralis, commonly known as zombie-ant fungus, is an insect-pathogenic fungus, discovered by the British naturalist Alfred Russel Wallace in 1859, and currently found predominantly in tropical forest ecosystems. O. unilateralis infects ants of the tribe Camponotini, with the full pathogenesis being characterized by alteration of the behavioral patterns of the infected ant. Infected hosts leave their canopy nests and foraging trails for the forest floor, an area with a temperature and humidity suitable for fungal growth; they then use their mandibles to attach themselves to a major vein on the underside of a leaf, where the host remains after its eventual death. The process, leading up to mortality, takes 4–10 days, and includes a reproductive stage where fruiting bodies grow from the ant's head, rupturing to release the fungus's spores. O. unilateralis is, in turn, also susceptible to fungal infection itself, an occurrence that can limit its impact on ant populations, which has otherwise been known to devastate ant colonies.

<span class="mw-page-title-main">Ophiocordycipitaceae</span> Family of fungi

Ophiocordycipitaceae is a family of parasitic fungi in the Ascomycota, class Sordariomycetes. It was updated in 2020.

<span class="mw-page-title-main">Fungi imperfecti</span> Fungal classification based on asexual characters when sexual reproduction is unidentified

The fungi imperfecti or imperfect fungi are fungi which do not fit into the commonly established taxonomic classifications of fungi that are based on biological species concepts or morphological characteristics of sexual structures because their sexual form of reproduction has never been observed. They are known as imperfect fungi because only their asexual and vegetative phases are known. They have asexual form of reproduction, meaning that these fungi produce their spores asexually, in the process called sporogenesis.

<i>Purpureocillium</i> Genus of fungi

Purpureocillium is a fungal genus in the Ophiocordycipitaceae family. The genus now contains at least 5 species with the type species Purpureocillium lilacinum, a common soil mold. It has been isolated from a wide range of habitats, including cultivated and uncultivated soils, forests, grassland, deserts, estuarine sediments and sewage sludge, and insects. It has also been found in nematode eggs, and occasionally from females of root-knot and cyst nematodes. In addition, it has frequently been detected in the rhizosphere of many crops. The species can grow at a wide range of temperatures – from 8 to 38 °C for a few isolates, with optimal growth in the range 26 to 30 °C. It also has a wide pH tolerance and can grow on a variety of substrates. P. lilacinum has shown promising results for use as a biocontrol agent to control the growth of destructive root-knot nematodes.

<i>Tolypocladium</i> Genus of fungi

Tolypocladium is a genus of fungi within the family Ophiocordycipitaceae. It includes species that are parasites of other fungi, insect pathogens, rotifer pathogens and soil inhabiting species with uncertain ecological roles. Tolypocladium was originally circumscribed as a genus containing anamorphic fungi. It was later determined that some Cordyceps-like teleomorphic fungi were the teleomorphs of Tolypocladium species. These species were considered to belong in the genus Cordyceps until molecular phylogenetics studies found these species to be more closely related to Ophiocordyceps and were considered to belong in that genus before they were transferred to the new genus Elaphocordyceps by Sung and colleagues in 2007. However, under the ICN's 2011 "one fungus, one name" principle, fungi can not have different names for their anamorphic and teleomorphic stages if they are found to be the same taxon. Quandt and colleagues formally synonymized Tolypocladium and Elaphocordyceps in 2014. Quandt and colleagues also synonymized the anamorphic genus Chaunopycnis with Tolypocladium. The immunosuppressant drug ciclosporin was originally isolated from Tolypocladium inflatum, and has since been found in other species of Tolypocladium, some of which were formerly placed in Chaunopycnis.

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

Aspergillus versicolor is a slow-growing species of filamentous fungus commonly found in damp indoor environments and on food products. It has a characteristic musty odor associated with moldy homes and is a major producer of the hepatotoxic and carcinogenic mycotoxin sterigmatocystin. Like other Aspergillus species, A. versicolor is an eye, nose, and throat irritant.

<span class="mw-page-title-main">Efrapeptin</span>

Efrapeptins are peptides produced by fungi in the genus Tolypocladium that have antifungal, insecticidal, and mitochondrial ATPase inhibitory activities. They are produced via a biosynthetic pathway similar to but simpler than the Ciclosporin pathway, with nonribosomal peptide synthase (NRPS) and/or polyketide synthase (PKS) being the key elements.

<i>Tolypocladium ophioglossoides</i> Species of fungus

Tolypocladium ophioglossoides, also known by two of its better known synonyms Elaphocordyceps ophioglossoides and Cordyceps ophioglossoides and commonly known as the goldenthread cordyceps, is a species of fungus in the family Ophiocordycipitaceae. It is parasitic on fruit bodies of the truffle-like Elaphomyces. The specific epithet ophioglossoides, derived from Ancient Greek, means "like a snake's tongue". The species is thought to be inedible by people in the Western hemisphere, however, Traditional Chinese medicine of the Eastern Hemisphere recognizes T. ophioglossoides as a valuable medicinal fungi.

<i>Cordyceps militaris</i> Species of fungus

Cordyceps militaris is a species of fungus in the family Cordycipitaceae, and the type species of the genus Cordyceps. It was originally described by Carl Linnaeus in 1753 as Clavaria militaris. There are hundreds of species of cordyceps fungi. Special characteristics of Cordyceps Militaris are its use in traditional Chinese medicine, modern pharmaceuticals, and its relationship with insects and how it disperses.

Medicinal fungi are fungi that contain metabolites or can be induced to produce metabolites through biotechnology to develop prescription drugs. Compounds successfully developed into drugs or under research include antibiotics, anti-cancer drugs, cholesterol and ergosterol synthesis inhibitors, psychotropic drugs, immunosuppressants and fungicides.

Trichoderma longibrachiatum is a fungus in the genus Trichoderma. In addition to being a distinct species, T. longibrachiatum also typifies one of several clades within Trichoderma which comprises 21 different species. Trichoderma longibrachiatum is a soil fungus which is found all over the world but mainly in warmer climates. Many species from this clade have been adopted in various industries because of their ability to secrete large amounts of protein and metabolites.

<i>Ophiocordyceps formicarum</i> Species of fungus

Ophiocordyceps formicarum is an entomopathogenic fungus belonging to the order Hypocreales (Ascomycota) in the family Ophiocordycipitaceae. The fungus was first described by mycologist George S. Kobayashi in 1939 as a species of Cordyceps. Originally found in Japan growing on an adult Hercules ant, it was reported from Guizhou, China, in 2003. It was transferred to the new genus Ophiocordyceps in 2007 when the family Cordycipitaceae was reorganized. A technique has been developed to grow the fungus in an agar growth medium supplemented with yeast extract, inosine, and glucose.

<i>Trichoderma koningii</i> Species of fungus

Trichoderma koningii is a very common soil dwelling saprotroph with a worldwide distribution. It has been heavily exploited for agricultural use as an effective biopesticide, having been frequently cited as an alternative biological control agent in the regulation of fungi-induced plant diseases. They are endosymbionts associated with plant root tissues, exhibiting mycoparasitism and promoting plant growth due to their capacity to produce different secondary metabolites.

<i>Cordyceps locustiphila</i> Species of fungus

Cordyceps locustiphila is the basionym and teleomorph of the fungi Beauveria locustiphila, a species of fungus in the family Cordycipitaceae. and is a species within the genus Cordyceps. It was originally described in by Henn in 1904. C. locustiphila is an entomopathogen and obligate parasite of the grasshopper species within the genus Colpolopha or Tropidacris, and as such is endemic to South America. The scientific name is derived from its close relationship with its host, being named after locusts. The fungi was renamed to Beauveria locustiphila in 2017 following research into the family Cordycipitaceae. Following the loss of the species type specimen, new studies were conducted that now recommend that the fungi be divided into 3 species. C. locustiphila, C. diapheromeriphila, and C. acridophila.


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