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{{Taxobox
| image =
| image_caption = ''Tolypocladium inflatum''
| regnum = [[Fungus|Fungi]]
| phylum = [[Ascomycota]]
| classis = [[Sordariomycetes]]
| subclassis = [[Sordariomycetidae]]
| ordo = [[Hypocreales]]
| familia = [[Ophiocordycipitaceae]]
| genus = ''[[Tolypocladium]]''
| species = '''''T. inflatum'''''
| binomial = ''Tolypocladium inflatum''
| binomial_authority = W. Gams (1971)
| synonyms = ''Pachybasium niveum'' <small>O. Rostr (1916)</small>
}}
'''''Tolypocladium inflatum''''' is an asexual [[ascomycete|ascomycetous]] [[fungus]] originally isolated from [[Norway|Norwegian]] [[soil]]. It is best known for producing the immunosuppressive and antimicrobial metabolite, [[cyclosporin]].<ref name="dhillon2002" />

==History==
In 1969, a soil sample containing microfungi from [[Norway]] was brought to [[Switzerland]]<ref name="dhillon2002">{{cite journal|last1=Dhillion|first1=Shivcharn S.|last2=Svarstad|first2=Hanne|last3=Amundsen|first3=Cathrine|last4=Bugge|first4=Hans Chr|title=Bioprospecting: Effects on Environment and Development|journal=AMBIO: A Journal of the Human Environment|date=September 2002|volume=31|issue=6|pages=491–493|doi=10.1579/0044-7447-31.6.491}}</ref> from which a fungus misidentified as ''Trichoderma polysporum'' was isolated.<ref>Dreyfuss M, Härri E, Hofmann H, Kobel H, Pache W, Tscherter H. (1976). "Cyclosporin A and C: new metabolites from ''Trichoderma polysporum'' (Link ex Pers.) Rifai". ''European Journal of Applied Microbiology'' '''3''': 125&ndash;133.</ref> In 1971 the Austrian mycologist, Walter Gams, re-identified the isolate as a previously unknown microfungus affiliated with the order Hypocreales.<ref name="bissett1983" /> He erected the genus ''Tolypocladium'' to accommodate the isolate which he named ''T. inflatum'' Gams.<ref name="bissett1983" /> The taxon is characterized by swollen [[Phialide|phialides]], sparingly branched [[conidiophores]], and small, [[unicellular]] [[conidia]] corne in slimy heads.<ref name="bissett1983">{{cite journal|last1=Bissett|first1=J.|title=Notes on Tolypocladium and related genera|journal=Canadian Journal of Botany|date=1983|pages=1311–1329|doi=10.1139/b83-139}}</ref> 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''.<ref>Bissett J. (1983). "Notes on ''Tolypocladium'' and related genera". ''Canadian Journal of Botany'' '''61''': 1311&ndash;1329.</ref> 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 [[nomen conservandum|conserve]] the name ''T. inflatum'' against earlier names was made and accepted, establishing the [[correct name (botany)|correct name]] of the mold that produces cyclosporin as ''Tolypocladium inflatum''.

==Growth and morphology==
''Tolypocladium inflatum'' is occurs most commonly in soil or leaf litter, particularly at high latitudes in cold soils.<ref name="bissett1983" /> The [[species]] is characterized by spherically swollen [[Phialide|phialides]] that are terminated with narrow necks bearing subglobose [[conidia]]. <ref name="bissett1983" /> ''Tolypocladium inflatum'' is highly tolerant of [[Lead|lead (Pb)]] and has been found to dominate the mycota of lead-contaminated soils.<ref name="baath2005" /> A study conducted by Baath ''et al''. found that 35% of the fungal isolates recovered from lead-laden soil were ''T. inflatum''.<ref name="baath2005">{{cite journal|last1=Bååth|first1=E.|last2=Díaz-Raviña|first2=M.|last3=Bakken|first3=L. R.|title=Microbial Biomass, Community Structure and Metal Tolerance of a Naturally Pb-Enriched Forest Soil|journal=Microbial Ecology|date=24 November 2005|volume=50|issue=4|pages=496–505|doi=10.1007/s00248-005-0008-3}}</ref> In 1996, Canadian mycologist Kathie Hodge and colleagues determined the mold ''T. inflatum'' is the asexual state of [[Elaphocordyceps subsessilis|''Elaphocordyceps'' (formerly ''Cordyceps'') ''subsessilis'']].<ref>Hodge KT, Krasnoff SB, Humber RA. (1996). "''Tolypocladium inflatum'' is the anamorph of ''Cordyceps subsessilis''". ''[[Mycologia]]'' '''88''': 715&ndash;719.</ref> Whereas the sexual ''Elaphocordyceps subsessilis'' state is a pathogen of beetles, the asexual ''T. inflatum'' state is widely distributed in soils.

==Metabolite production==
''Tolypocladium inflatum'' is similar to other fungi in the order Hypocreales in generating a variety of biologically active [[secondary metabolites]].<ref name="bushley2013" /> Two significant groups of metabolites are produced from ''T. inflatum'': [[cyclosporins]] and [[efrapeptin|efrapeptins]].<ref name="hodge1996" /> Cyclosporin exhibits [[insecticidal]] and [[antifungal]] properties<ref name="hodge1996" /> and is a key [[immunosuppressant]] drug used to prevent the rejection of transplanted organs.<ref name="bushley2013" /> [[Cyclosporin A]] also has the potential use in the treatment of [[autoimmune diseases]].<ref name="hodge1996" /> The [[genome]] of [[filamentous]] ''T. inflatum'' contains a repetitive [[cyclosporin A]] element.<ref name="kempken2008">{{cite journal|date=December 2008|title=The element encodes a RecQ helicase-like gene|journal=Journal of Basic Microbiology|volume=48|issue=6|pages=496–499|doi=10.1002/jobm.200800164|last1=Kempken|first1=Frank}}</ref> [[Efrapeptin|Efrapeptins]] are mitochondrial and prokaryotic [[ATPase]] inhibitors that also have insecticidal and antifungal properties. <ref name="hodge1996" /> Little is known about the role of these metabolites in the ecology of the fungus.<ref name="hodge1996" /> 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.<ref name="lin2011">{{cite journal|last1=Lin|first1=Jie|last2=Chen|first2=Xiaoyan|last3=Cai|first3=Xiaoyue|last4=Yu|first4=Xinfang|last5=Liu|first5=Xingzhong|last6=Cao|first6=Ya|last7=Che|first7=Yongsheng|title=Isolation and Characterization of Aphidicolin and Chlamydosporol Derivatives from Tolypocladium inflatum|journal=Journal of Natural Products|date=26 August 2011|volume=74|issue=8|pages=1798–1804|doi=10.1021/np200431k}}</ref>

==Pathogenicity==
Although ''Tolypocladium inflatum'' is chiefly as a soil fungus<ref name="bushley2013" /> its sexual state has been encountered as a pathogen of insects<ref name="hodge1996">{{cite journal|last1=Hodge|first1=Kathie T.|last2=Krasnoff|first2=Stuart B.|last3=Humber|first3=Richard A.|title=Tolypocladium inflatum Is the Anamorph of Cordyceps subsessilis|journal=Mycologia|date=September 1996|volume=88|issue=5|pages=715|doi=10.2307/3760965}}</ref>, specifically [[Beetle|beetle]] [[larvae]].<ref name="bushley2013" /> 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]].<ref name="hodge1996">{{cite journal|last1=Hodge|first1=Kathie T.|last2=Krasnoff|first2=Stuart B.|last3=Humber|first3=Richard A.|title=Tolypocladium inflatum Is the Anamorph of Cordyceps subsessilis|journal=Mycologia|date=September 1996|volume=88|issue=5|pages=715|doi=10.2307/3760965}}</ref> 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.<ref name="hodge1996">{{cite journal|last1=Hodge|first1=Kathie T.|last2=Krasnoff|first2=Stuart B.|last3=Humber|first3=Richard A.|title=Tolypocladium inflatum Is the Anamorph of Cordyceps subsessilis|journal=Mycologia|date=September 1996|volume=88|issue=5|pages=715|doi=10.2307/3760965}}</ref> ''Tolypocladium inflatum'' has also shown to produce substances that inhibit the [[in vitro]] growth of a number of fungal species. <ref name"summerbell1987">{{cite journal|last1=SUMMERBELL|first1=RICHARD C.|title=THE INHIBITORY EFFECT OF TRICHODERMA SPECIES AND OTHER SOIL MICROFUNGI ON FORMATION OF MYCORRHIZA BY LACCARIA BICOLOR IN VITRO|journal=New Phytologist|date=March 1987|volume=105|issue=3|pages=437–448|doi=10.1111/j.1469-8137.1987.tb00881.x}}</ref> Some suggest that ''T. inflatum'' may also have the ability to inhibit certain fungal plant pathogens from colonizing their hosts.<ref name="summerbell1987" /> For example, ''T. inflatum'' had a small but significant effect on inhibiting [[mycorrhiza]] formation.<ref name="summerbell1987" /> Furthermore, [[secondary metabolites]] isolated from the crude extract of ''T. inflatum'' have shown modest [[cytotoxicity]] against eight human [[tumour]] cell lines including [[A549 cell|A549]] (human lung [[adenocarcinoma]]), A375 (human malignant [[melanoma]]), and [[MCF-7]] (human [[breast cancer]]).<ref name="lin2011" />

==Medical uses==
''Tolypocladium inflatum'' has long been of interest in biotechnology due to its production of a relatively non-cytotoxic, natural 11 [[amino acid]]<ref name="simons1986">{{cite journal|last1=Simons|first1=J. W.|title=Cyclosporine A, an in vitro calmodulin antagonist, induces nuclear lobulations in human T cell lymphocytes and monocytes|journal=The Journal of Cell Biology|date=1 January 1986|volume=102|issue=1|pages=145–150|doi=10.1083/jcb.102.1.145}}</ref> [[cyclic peptide]]<ref name="disalvo2013">{{cite journal|last1=di Salvo|first1=Martino L.|last2=Florio|first2=Rita|last3=Paiardini|first3=Alessandro|last4=Vivoli|first4=Mirella|last5=D’Aguanno|first5=Simona|last6=Contestabile|first6=Roberto|title=Alanine racemase from Tolypocladium inflatum: A key PLP-dependent enzyme in cyclosporin biosynthesis and a model of catalytic promiscuity|journal=Archives of Biochemistry and Biophysics|date=January 2013|volume=529|issue=2|pages=55–65|doi=10.1016/j.abb.2012.11.011}}</ref> named [[Cyclosporin A]].<ref name="bushley2013">{{cite journal|last1=Bushley|first1=Kathryn E.|last2=Raja|first2=Rajani|last3=Jaiswal|first3=Pankaj|last4=Cumbie|first4=Jason S.|last5=Nonogaki|first5=Mariko|last6=Boyd|first6=Alexander E.|last7=Owensby|first7=C. Alisha|last8=Knaus|first8=Brian J.|last9=Elser|first9=Justin|last10=Miller|first10=Daniel|last11=Di|first11=Yanming|last12=McPhail|first12=Kerry L.|last13=Spatafora|first13=Joseph W.|last14=Heitman|first14=Joseph|title=The Genome of Tolypocladium inflatum: Evolution, Organization, and Expression of the Cyclosporin Biosynthetic Gene Cluster|journal=PLoS Genetics|date=20 June 2013|volume=9|issue=6|pages=e1003496|doi=10.1371/journal.pgen.1003496}}</ref> Cyclosporin is an [[immunosuppressant drug]] used in the management of [[autoimmune diseases]] and the prevention of rejection in organ transplantation.<ref name="dhillon2002">{{cite journal|last1=Dhillion|first1=Shivcharn S.|last2=Svarstad|first2=Hanne|last3=Amundsen|first3=Cathrine|last4=Bugge|first4=Hans Chr|title=Bioprospecting: Effects on Environment and Development|journal=AMBIO: A Journal of the Human Environment|date=September 2002|volume=31|issue=6|pages=491–493|doi=10.1579/0044-7447-31.6.491}}</ref> [[Cyclosporin A]] works by targeting and binding with human [[cyclophilin A]].<ref name="bushley2013" /> This cyclosporine-cyclophilin binding inhibits [[calcineurin]] and effectively inhibits the human [[immune system]].<ref name="bushley2013" /> Without calcineurin, the activity of nuclear factor of activated [[T-cells]] and [[transcription regulator|transcription regulators]] of [[Interleukin 2|IL-2]] in [[T-lymphocytes]] is blocked.<ref name="bushley2013" /> Cyclosporin A considerably alters the nuclear morphology of in vitro human peripheral blood [[mononuclear leukocytes]] from [[ovoid]] to a radially splayed [[lobulated]] structure.<ref name="simons1986">{{cite journal|last1=Simons|first1=J. W.|title=Cyclosporine A, an in vitro calmodulin antagonist, induces nuclear lobulations in human T cell lymphocytes and monocytes|journal=The Journal of Cell Biology|date=1 January 1986|volume=102|issue=1|pages=145–150|doi=10.1083/jcb.102.1.145}}</ref> The expression levels of alanine racemase affects the level of cyclosporine production by ''T. inflatum''.<ref name="disalvo2013" /> Cyclosporin A was first introduced in medical use in the 1970s after an organ transplant to reduce [[graft rejection]].<ref name="hoppert2001">{{cite journal|last1=Hoppert|first1=Michael|last2=Gentzsch|first2=Carsten|last3=Schorgendorfer|first3=Kurt|title=Structure and localization of cyclosporin synthetase, the key enzyme of cyclosporin biosynthesis in Tolypocladium inflatum|journal=Archives of Microbiology|date=1 October 2001|volume=176|issue=4|pages=285–293|doi=10.1007/s002030100324}}</ref> This use was based on cyclosporin’s ability to interfere with [[lymphokine]] [[biosynthesis]].<ref name="hoppert2001">{{cite journal|last1=Hoppert|first1=Michael|last2=Gentzsch|first2=Carsten|last3=Schorgendorfer|first3=Kurt|title=Structure and localization of cyclosporin synthetase, the key enzyme of cyclosporin biosynthesis in Tolypocladium inflatum|journal=Archives of Microbiology|date=1 October 2001|volume=176|issue=4|pages=285–293|doi=10.1007/s002030100324}}</ref> Cyclosporin 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]].<ref name="disalvo2013" /> Despite its use in medicine, cyclosporine A exhibits significant [[nephrotoxicity]], [[cardiotoxicity]], and pathotoxicity.<ref name="larson1993">{{cite journal|last1=Larson|first1=T. G.|last2=Nuss|first2=D. L.|title=Cyclophilin-dependent stimulation of transcription by cyclosporin A.|journal=Proceedings of the National Academy of Sciences|date=1 January 1993|volume=90|issue=1|pages=148–152|doi=10.1073/pnas.90.1.148}}</ref> Drugs containing ''T. inflatum''-produced cyclosporin A are a major product of the pharmaceutical company, [[Novartis]].<ref name="dhillon2002" />

==References==

{{Reflist|30em|refs=

<ref name="bissett1983">{{cite journal|last1=Bissett|first1=J.|title=Notes on Tolypocladium and related genera|journal=Canadian Journal of Botany|date=1983|pages=1311–1329|doi=10.1139/b83-139}}</ref>

<ref name="bushley2013">{{cite journal|last1=Bushley|first1=Kathryn E.|last2=Raja|first2=Rajani|last3=Jaiswal|first3=Pankaj|last4=Cumbie|first4=Jason S.|last5=Nonogaki|first5=Mariko|last6=Boyd|first6=Alexander E.|last7=Owensby|first7=C. Alisha|last8=Knaus|first8=Brian J.|last9=Elser|first9=Justin|last10=Miller|first10=Daniel|last11=Di|first11=Yanming|last12=McPhail|first12=Kerry L.|last13=Spatafora|first13=Joseph W.|last14=Heitman|first14=Joseph|title=The Genome of Tolypocladium inflatum: Evolution, Organization, and Expression of the Cyclosporin Biosynthetic Gene Cluster|journal=PLoS Genetics|date=20 June 2013|volume=9|issue=6|pages=e1003496|doi=10.1371/journal.pgen.1003496}}</ref>

<ref name="baath2005">{{cite journal|last1=Bååth|first1=E.|last2=Díaz-Raviña|first2=M.|last3=Bakken|first3=L. R.|title=Microbial Biomass, Community Structure and Metal Tolerance of a Naturally Pb-Enriched Forest Soil|journal=Microbial Ecology|date=24 November 2005|volume=50|issue=4|pages=496–505|doi=10.1007/s00248-005-0008-3}}</ref>

<ref name="dhillon2002">{{cite journal|last1=Dhillion|first1=Shivcharn S.|last2=Svarstad|first2=Hanne|last3=Amundsen|first3=Cathrine|last4=Bugge|first4=Hans Chr|title=Bioprospecting: Effects on Environment and Development|journal=AMBIO: A Journal of the Human Environment|date=September 2002|volume=31|issue=6|pages=491–493|doi=10.1579/0044-7447-31.6.491}}</ref>

<ref name="disalvo2013">{{cite journal|last1=di Salvo|first1=Martino L.|last2=Florio|first2=Rita|last3=Paiardini|first3=Alessandro|last4=Vivoli|first4=Mirella|last5=D’Aguanno|first5=Simona|last6=Contestabile|first6=Roberto|title=Alanine racemase from Tolypocladium inflatum: A key PLP-dependent enzyme in cyclosporin biosynthesis and a model of catalytic promiscuity|journal=Archives of Biochemistry and Biophysics|date=January 2013|volume=529|issue=2|pages=55–65|doi=10.1016/j.abb.2012.11.011}}</ref>

<ref name="hodge1996">{{cite journal|last1=Hodge|first1=Kathie T.|last2=Krasnoff|first2=Stuart B.|last3=Humber|first3=Richard A.|title=Tolypocladium inflatum Is the Anamorph of Cordyceps subsessilis|journal=Mycologia|date=September 1996|volume=88|issue=5|pages=715|doi=10.2307/3760965}}</ref>

<ref name="hoppert2001">{{cite journal|last1=Hoppert|first1=Michael|last2=Gentzsch|first2=Carsten|last3=Schorgendorfer|first3=Kurt|title=Structure and localization of cyclosporin synthetase, the key enzyme of cyclosporin biosynthesis in Tolypocladium inflatum|journal=Archives of Microbiology|date=1 October 2001|volume=176|issue=4|pages=285–293|doi=10.1007/s002030100324}}</ref>

<ref name="kempken2008">{{cite journal|last1=Kempken|first1=Frank|title=The element encodes a RecQ helicase-like gene|journal=Journal of Basic Microbiology|date=December 2008|volume=48|issue=6|pages=496–499|doi=10.1002/jobm.200800164}}</ref>

<ref name="larson1993">{{cite journal|last1=Larson|first1=T. G.|last2=Nuss|first2=D. L.|title=Cyclophilin-dependent stimulation of transcription by cyclosporin A.|journal=Proceedings of the National Academy of Sciences|date=1 January 1993|volume=90|issue=1|pages=148–152|doi=10.1073/pnas.90.1.148}}</ref>

<ref name="lin2011">{{cite journal|last1=Lin|first1=Jie|last2=Chen|first2=Xiaoyan|last3=Cai|first3=Xiaoyue|last4=Yu|first4=Xinfang|last5=Liu|first5=Xingzhong|last6=Cao|first6=Ya|last7=Che|first7=Yongsheng|title=Isolation and Characterization of Aphidicolin and Chlamydosporol Derivatives from Tolypocladium inflatum|journal=Journal of Natural Products|date=26 August 2011|volume=74|issue=8|pages=1798–1804|doi=10.1021/np200431k}}</ref>

<ref name="simons1986">{{cite journal|last1=Simons|first1=J. W.|title=Cyclosporine A, an in vitro calmodulin antagonist, induces nuclear lobulations in human T cell lymphocytes and monocytes|journal=The Journal of Cell Biology|date=1 January 1986|volume=102|issue=1|pages=145–150|doi=10.1083/jcb.102.1.145}}</ref>

<ref name="summerbell1987">{{cite journal|last1=Summerbell|first1=Richard C.|title=The Inhibitory Effect Of Trichoderma Species And Other Soil Microfungi On Formation Of Mycorrhiza By Laccaria Bicolor In Vitro|journal=New Phytologist|date=March 1987|volume=105|issue=3|pages=437–448|doi=10.1111/j.1469-8137.1987.tb00881.x}}</ref>

<ref name=barron1968>{{cite book|last1=Barron|first1=George L.|title=The genera of Hyphomycetes from soil|date=1968|publisher=Williams & Wilkins|location=Baltimore, MD|isbn=9780882750040}}</ref>

<ref name=domsch1980>{{cite book|last1=Domsch|first1=K.H.|last2=Gams|first2=Walter|last3=Andersen|first3=Traute-Heidi|title=Compendium of soil fungi|year=1980|publisher=Academic Press|location=London, UK|isbn=9780122204029|edition=2nd}}</ref>

<ref name=howard2007>{{cite book|last1=Howard|first1=Dexter H.|title=Pathogenic fungi in humans and animals|year=2007|publisher=Dekker|location=New York, NY|isbn=0824706838|edition=2nd}}</ref>

<ref name=kane1997>{{cite book|last1=Kane|first1=Julius|last2=Summerbell|first2=Richard|last3=Sigler|first3=Lynne|last4=Krajden|first4=Sigmund|last5=Land|first5=Geoffrey|title=Laboratory handbook of dermatophytes: a clinical guide and laboratory handbook of dermatophytes and other filamentous fungi from skin, hair, and nails|year=1997|publisher=Star Pub.|location=Belmont, CA|isbn=978-0898631579}}</ref>

<ref name=kwon-chung1992>{{cite book|last1=Kwon-Chung|first1=K. June|last2=Bennett|first2=Joan E.|title=Medical mycology|year=1992|publisher=Lea & Febiger|location=Philadelphia|isbn=0812114639}}</ref>

<ref name=onions1981>{{cite book|last1=Onions|first1=A.H.S.|last2=Allsopp|first2=D.|last3=Eggins|first3=H.O.W.|title=Smith's introduction to industrial mycology|date=1981|publisher=Arnold|location=London, UK|isbn=0-7131-2811-9|edition=7th}}</ref>

<ref name=rippon1988>{{cite book|last=Rippon|first=John Willard|title=Medical mycology: the pathogenic fungi and the pathogenic actinomycetes|year=1988|publisher=Saunders|location=Philadelphia, PA|isbn=0721624448|edition=3rd}}</ref>

}}

{{DEFAULTSORT:Tolypocladium inflatum}}
[[:Category:Ophiocordycipitaceae]]
[[:Category:Fungi of Europe]]