Tolypocladium Inflatum
   HOME

TheInfoList



OR:

''Tolypocladium inflatum'' is an ascomycete
fungus A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...
originally isolated from a Norwegian soil sample that, under certain conditions, produces the
immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system. Classification Immunosuppressive drugs can be classified ...
drug
ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...
. 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 A mold () or mould () is one of the structures that certain fungus, fungi can form. The dust-like, colored appearance of molds is due to the formation of Spore#Fungi, spores containing Secondary metabolite#Fungal secondary metabolites, fungal ...
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''.


History

In 1969, a soil sample containing
microfungi Microfungi or micromycetes are fungi—eukaryotic organisms such as molds, mildews and rusts—which have microscopic spore-producing structures. They exhibit tube tip-growth and have cell walls composed of chitin, a polymer of ''N''-acetylgluco ...
from Norway, found by Hans Peter Frey. was brought to Switzerland from which a fungus misidentified as ''Trichoderma polysporum'' was isolated. In 1971 the Austrian mycologist, Walter Gams, re-identified the isolate as a previously unknown microfungus affiliated with the order
Hypocreales The Hypocreales are an order of fungi within the class Sordariomycetes. In 2008, it was estimated that it contained some 237 genera, and 2647 species in seven families. Since then, a considerable number of further taxa have been identified, in ...
. He erected the genus '' Tolypocladium'' to accommodate the isolate which he named ''T. inflatum'' Gams. The taxon is characterized by swollen phialides, sparingly branched conidiophores, and small,
unicellular A unicellular organism, also known as a single-celled organism, is an organism that consists of a single cell, unlike a multicellular organism that consists of multiple cells. Organisms fall into two general categories: prokaryotic organisms and ...
conidia A conidium ( ; : conidia), sometimes termed an asexual chlamydospore or chlamydoconidium (: chlamydoconidia), is an asexual, non- motile spore of a fungus. The word ''conidium'' comes from the Ancient Greek word for dust, ('). They are also ...
borne in slimy heads. 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 Botanical nomenclature is the formal, scientific naming of plants. It is related to, but distinct from taxonomy (biology), taxonomy. Plant taxonomy is concerned with grouping and classifying plants; Botany, botanical nomenclature then provides na ...
, Bissett proposed the combination ''Tolypocladium niveum''. 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 Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...
as ''Tolypocladium inflatum''.


Growth and morphology

''Tolypocladium inflatum'' occurs most commonly in soil or leaf litter, particularly at high latitudes in cold soils. The
species A species () is often defined as the largest group of organisms in which any two individuals of the appropriate sexes or mating types can produce fertile offspring, typically by sexual reproduction. It is the basic unit of Taxonomy (biology), ...
is characterized by spherically swollen phialides that are terminated with narrow necks bearing subglobose
conidia A conidium ( ; : conidia), sometimes termed an asexual chlamydospore or chlamydoconidium (: chlamydoconidia), is an asexual, non- motile spore of a fungus. The word ''conidium'' comes from the Ancient Greek word for dust, ('). They are also ...
. ''T. inflatum'' is highly tolerant of
lead Lead () is a chemical element; it has Chemical symbol, symbol Pb (from Latin ) and atomic number 82. It is a Heavy metal (elements), heavy metal that is density, denser than most common materials. Lead is Mohs scale, soft and Ductility, malleabl ...
and has been found to dominate the mycota of lead-contaminated soils. A study conducted by Baath ''et al''. found that 35% of the fungal isolates recovered from lead-laden soil were ''T. inflatum''. In 1996, Kathie Hodge of
Cornell University Cornell University is a Private university, private Ivy League research university based in Ithaca, New York, United States. The university was co-founded by American philanthropist Ezra Cornell and historian and educator Andrew Dickson W ...
and colleagues determined that the mold ''T. inflatum'' was the asexual state of what was then known as ''Cordyceps subsessilis''. ''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''. The genome of the ''T. inflatum'' strain/isolate NRRL 8044 (ATCC 34921) was sequenced and published in 2013 by Bushley and colleagues. 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 Secondary metabolites, also called ''specialised metabolites'', ''secondary products'', or ''natural products'', are organic compounds produced by any lifeform, e.g. bacteria, archaea, fungi, animals, or plants, which are not directly involved ...
. Two significant groups of metabolites are produced from ''T. inflatum'': ciclosporins and efrapeptins. Ciclosporin exhibits insecticidal and
antifungal An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as ...
properties and is a key
immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system. Classification Immunosuppressive drugs can be classified ...
drug used to prevent the rejection of transplanted organs. Ciclosporin A also has the potential use in the treatment of
autoimmune diseases An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that ...
. The
genome A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...
of filamentous ''T. inflatum'' contains a 12-gene cluster associated with a repetitive element. Efrapeptins are mitochondrial and prokaryotic
ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, ATP hydrolase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or ...
inhibitors that also have insecticidal and antifungal properties. Little is known about the role of these metabolites in the ecology of the fungus. 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.


Pathogenicity

Although ''Tolypocladium inflatum'' is chiefly as a soil fungus its sexual state has been encountered as a pathogen of insects and mite pests, specifically
beetle Beetles are insects that form the Taxonomic rank, order Coleoptera (), in the superorder Holometabola. Their front pair of wings are hardened into wing-cases, elytra, distinguishing them from most other insects. The Coleoptera, with about 40 ...
larvae A larva (; : larvae ) is a distinct juvenile form many animals undergo before metamorphosis into their next life stage. Animals with indirect developmental biology, development such as insects, some arachnids, amphibians, or cnidarians typical ...
and Two-spotted spider mite. 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. Although ''T. inflatum'' has not been shown to affect
nematodes The nematodes ( or ; ; ), roundworms or eelworms constitute the phylum Nematoda. Species in the phylum inhabit a broad range of environments. Most species are free-living, feeding on microorganisms, but many are parasitic. Parasitic worms (he ...
, researchers Samson and Soares hypothesized that the ''Tolypocladium'' species may have a nematode alternate host. ''Tolypocladium inflatum'' has also shown to produce substances that inhibit the
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
growth of a number of fungal species. Some suggest that ''T. inflatum'' may also have the ability to inhibit certain fungal plant pathogens from colonizing their hosts. For example, ''T. inflatum'' had a small but significant effect on inhibiting
mycorrhiza A mycorrhiza (; , mycorrhiza, or mycorrhizas) is a symbiotic association between a fungus and a plant. The term mycorrhiza refers to the role of the fungus in the plant's rhizosphere, the plant root system and its surroundings. Mycorrhizae play ...
formation. Furthermore,
secondary metabolites Secondary metabolites, also called ''specialised metabolites'', ''secondary products'', or ''natural products'', are organic compounds produced by any lifeform, e.g. bacteria, archaea, fungi, animals, or plants, which are not directly involved ...
isolated from the crude extract of ''T. inflatum'' have shown modest
cytotoxicity Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of d ...
against eight human
tumour A neoplasm () is a type of abnormal and excessive growth of tissue (biology), tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tiss ...
cell lines including A549 (human lung
adenocarcinoma Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ; AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...
), A375 (human malignant
melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...
), and
MCF-7 MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-workers ...
(human
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
).


Medical uses

''Tolypocladium inflatum'' has long been of interest in biotechnology due to its production of a relatively non-cytotoxic, natural 11
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
cyclic peptide Cyclic peptides are polypeptide chains which contain a circular sequence of bonds. This can be through a connection between the amino and carboxyl ends of the peptide, for example in cyclosporin; a connection between the amino end and a side cha ...
named Ciclosporin A. Ciclosporin is an immunosuppressant drug used in the management of
autoimmune diseases An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that ...
and the prevention of rejection in organ transplantation. Ciclosporin A works by targeting and binding with human ciclophilin A. This ciclosporine-ciclophilin binding inhibits
calcineurin Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase). It activates the T cells of the immune system and can be block ...
and effectively inhibits the human
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
. Without calcineurin, the activity of nuclear factor of activated
T-cells T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
and transcription regulators of
IL-2 The Ilyushin Il-2 (Russian language, Russian: Илью́шин Ил-2) is a Ground attack aircraft, ground-attack plane that was produced by the Soviet Union in large numbers during the World War II, Second World War. The word ''shturmovík'' (C ...
in T-lymphocytes is blocked. Ciclosporin A considerably alters the nuclear morphology of in vitro human peripheral blood mononuclear leukocytes from
ovoid An oval () is a closed curve in a plane which resembles the outline of an egg. The term is not very specific, but in some areas of mathematics (projective geometry, technical drawing, etc.), it is given a more precise definition, which may inc ...
to a radially splayed lobulated structure. The expression levels of alanine racemase affects the level of cyclosporine production by ''T. inflatum''. Ciclosporin A was first introduced in medical use in the 1970s after an organ transplant to reduce graft rejection. This use was based on cyclosporin’s ability to interfere with
lymphokine Lymphokines are a subset of cytokines that are produced by a type of immune cell known as a lymphocyte. They are protein mediators typically produced by T cells to direct the immune system response by signaling between its cells. Lymphokines have ...
biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...
. Ciclosporin A also has
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...
,
antifungal An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as ...
, and
antiparasitic Antiparasitics are a class of medications which are indicated for the treatment of parasitic diseases, such as those caused by helminths, amoeba, ectoparasites, parasitic fungi, and protozoa, among others. Antiparasitics target the parasitic ...
abilities. It has been recommended for autoimmune diseases as well as potential treatment for
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
, type I diabetes, and
HIV-1 The subtypes of HIV include two main subtypes, known as HIV type 1 (HIV-1) and HIV type 2 (HIV-2). These subtypes have distinct genetic differences and are associated with different epidemiological patterns and clinical characteristics. HIV-1 e ...
. Despite its use in medicine, cyclosporine A exhibits significant
nephrotoxicity Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxin ...
, cardiotoxicity, and hepathotoxicity. Drugs containing ''T. inflatum''-produced cyclosporin A are a major product of the pharmaceutical company,
Novartis Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...
.


References

{{DEFAULTSORT:Tolypocladium inflatum Ophiocordycipitaceae Fungi of Europe Parasitic fungi Fungi described in 1916 Fungus species