Druzhinin A

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Species of the fiamentous-ascomycete genus Trichodermaare among the most commony isoated saprotrophicfungi. They are frequenty found in soi and growingon wood, bark, other fungi and innumerabe other sub-strates, demonstrating their high opportunistic potentiaand their adaptabiity to various ecoogica conditions14.The nomencature of these fungi (BOX 1) is compicatedbecause of their peiomorphism that is, some ofthem can exist in two morphoogicay and physioogi-cay different stages. The sexua (teeomorphic) stageis known by the generic name Hypocrea, whereas theasexua (anamorphic or mitosporic) stage is caedTrichoderma; here, we refer to the genus coectiveyas Hypocrea/Trichoderma. Athough severa commonspecies have ost their abiity to reproduce sexuayand have become cona species (or agamospecies; forexampe, Trichoderma longibrachiatum, Trichodermaharzianum and Trichoderma parareesei)58, the majority

of the genetic diversity of the genus is represented bysexua forms3,4,9,10, and some species are isoated equayfrequenty as both anamorphs and teeomorphs.

Most fruiting bodies ofHypocrea spp. are foundassociated with specific basidiomycete fungi; for exam-pe, Hypocrea estonica and Hypocrea parestonica awaysgrow on Hymenochaete spp., Hypocrea fomiticola isfound on Fomes fomentarius, and Hypocrea pulvinatagrows on Fomitopsis pinicola and Piptoporus betulinus(FIG. 1). Mycoparasitic species ofHypocrea/Trichodermacan degrade and grow within the resting structures(scerotia) that are produced by a wide variety of pant-pathogenic fungi, such as Sclerotinia spp., Typhula spp.,

Macrophomina phaseolina and Verticillium dahliae11.These data support the hypothesis of Rossman et al.12that Hypocrea spp. and some other members of theHypocreaes evoved as biotrophic associates (that is,parasites, in a broad sense of the word) of wood-rottingfungi and ater on expored the wood as an optiona eco-ogica niche. Some species such as Hypocreajecorina/Trichoderma reesei13, an important industria producerof ceuoytic and hemicellulolytic enzymes14, may haveswitched to iving on the pre-degraded wood rather thanthe host fungus itsef13. Thus, the abiity to antagonize,parasitize or even ki other fungi seems to be widespreadamong Hypocrea/Trichoderma spp. This property wasthe reason why researchers and industry started testingand using Hypocrea/Trichoderma strains for the antago-nization and eventua kiing of pant pathogens15,16 (thatis, for bioogica contro, or biocontro).

Athough the genus Hypocrea/Trichoderma contains

many species3,4,9,10, most research on mycoparasitism hasbeen performed with ony a few of these species, suchas T. cf. harzianum sensu ato, Hypocrea atroviridis/Trichoderma atroviride, Hypocrea virens/Trichodermavirens, Trichoderma asperellum and Trichodermaasperelloides15,16. In the course of these studies, it wasobserved that Hypocrea/Trichoderma strains that areused for biocontro can estabish themseves in thepant rhizosphere, stimuate pant growth and eicitpant defence reactions against pathogens1517. Moreover,some Hypocrea/Trichoderma strains were isoated asendophytes (that is, as coonizers of interceuar pantcompartments)18.

*Area Gene Technology and

Applied Biochemistry, Institute

of Chemical Engineering,

Vienna University of Technology,

1060 Vienna, Austria.Laboratorio Nacional de

Genmica para la Biodiversidad,

Cinvestav Campus Guanajuato,

36821, Irapuato, Guanajuato,

Mexico.Department of Biology,

Technion - Israel Institute of

Technology, Haifa 32000, Israel.||Department of Plant Pathology

and Microbiology, Texas A&M

University, College Station,

Texas 77843, USA.Spanish-Portuguese Centre for

Agricultural Research (CIALE),

Department of Microbiology and

Genetics, University of Salamanca,

Salamanca 370007, Spain.#Nuclear Agriculture and

Biotechnology Division, BhabhaAtomic Research Centre, Trombay,

Mumbai 400085, India.

**Department of Energy

Joint Genome Institute, Walnut

Creek, California 94598, USA.Present address: Central

Institute for Cotton Research,

Shankarnagar, Nagpur 440010,

India.

Correspondence to C.P.K.

e-mail: [email protected].

tuwien.ac.at

doi:10.1038/nrmicro2637

Corrected online

24 October 2011

Trichoderma: the genomics ofopportunistic successIrina S. Druzhinina*,Verena Seidl-Seiboth*, Alfredo Herrera-Estrella,

Benjamin A. Horwitz, Charles M. Kenerley||, Enrique Monte, Prasun K. Mukherjee#,

Susanne Zeilinger*, Igor V. Grigoriev** and Christian P. Kubicek*

Abstract | Trichoderma is a genus of common filamentous fungi that display a remarkable range

of lifestyles and interactions with other fungi, animals and plants. Because of their ability to

antagonize plant-pathogenic fungi and to stimulate plant growth and defence responses,some Trichodermastrains are used for biological control of plant diseases. In this Review, we

discuss recent advances in molecular ecology and genomics which indicate that the

interactions ofTrichoderma spp. with animals and plants may have evolved as a result of

saprotrophy on fungal biomass (mycotrophy) and various forms of parasitism on other fungi

(mycoparasitism), combined with broad environmental opportunism.

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NATURE REVIEWS |MICROBIOLOGY VOLUME 9 | OCTOBER 2011 |749

2011 Macmillan Publishers Limited. All rights reserved
mailto:[email protected]:[email protected]:[email protected]:[email protected]


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a

c

e f

d

b

FS

T

TFS

FS

H

H

H

H

H

H

FS

FS

FS

Figure 1 | Mycotrophy ofHypocrea/Trichoderma spp. Examples ofHypocrea/

Trichoderma spp. growing on various fungal substrates (FS).Hypocrea (H) is the sexual

stage (teleomorph) for the species, and in some cases the corresponding asexual stage

(anamorph; Trichoderma (T)) is present. a | Hypocreathelephoricolagrowing on

Steccherinum ochraceum. b | Hypocrea lixii and a Trichodermasp. growing on a Phellinus sp.

c | Hypocrea protopulvinata growing on a Fomitopsis sp.d | Hypocrea sulphurea growing

on an Exidia sp. e | Hypocrea parestonica and Trichoderma parestonicum growing on

a Hymenochaete sp. f| Hypocrea pulvinata growing on Piptoporus betulinus. Images

courtesy of Walter M. Jaklitsch, University of Vienna, Austria.

Saprotrophic

Using extracellular digestion

of dead or decayed organic

matter as a food source.

Opportunistic

Able to rapidly adapt to occupy

a newly arising ecological niche.

Biotrophic

Relying on another living

organism for nutrition. This

includes the broad spectrum

of parasitic, mutualistic and

commensalistic interactions.

Parasites

Organisms that take part in

inter-species biotrophic

interactions in which the

parasites benefit at the

expense of the other organisms

in the interaction (the hosts).

The recent sequencing of the genomes of two speciesthat are widey used in biocontro, H. atroviridis andH. virens13, and the advent of associated omic techno-ogies in Hypocrea/Trichoderma research19,20 have shednew ight on the ecoogy of the genus and the evou-tion of its traits. In this Review, we summarize recentinsights from the genomic anayses ofH. atroviridis andH. virens and emphasize that mycotrophy in a broadsense (incuding mycoparasitism) seems to be a wide-

spread property within the genus and a key to a better

understanding of the broad spectrum of opportunis-tic interactions with other organisms such as animasand pants.

A mosaic of mycotrophic interactionsThe direct interactions between Hypocrea/Trichodermaspp. and other fungi are conventionay described asnecrotrophic hyperparasitism or mycoparasitism17.This view is supported by a recent survey of >1,100

Hypocrea/Trichoderma strains from 75 moecuarydefined species, which showed that a the species testedpossess mycoparasitic potentia against three causativeagents of pant diseases:Alternaria alternata, Botryotiniafuckeliana (anamorph Botrytis cinerea) and Sclerotiniasclerotiorum (I.S.D., unpubished observations).However, because Hypocrea/Trichoderma spp. can asofeed on dead funga biomass, the ifestye of the genusmay be better defined as mycotrophic rather than myco-parasitic, to incude both biotrophic and saprotrophicnutritiona strategies.

Sensing the presence of the prey. Genomic sequencingof three Hypocrea/Trichoderma spp. (that is, H. jecorina,H. virens and H. atroviridis)13 and the appication of tran-scriptomics19,20 have recenty provided severa importantinsights into the moecuar physioogy of mycotrophy.Many genes that encode proteases and oigopeptidetransporters are expressed before and during contactwith the prey in different Hypocrea/Trichoderma spp.20,21.Most of these proteases beong to the subtiisin-ike ser-ine protease group, and genes encoding these enzymesare significanty over-represented in expressed sequencetags (ESTs) derived from T. cf. harzianum CECT 2413grown under biocontro conditions21. An abundanceof genes encoding subtiisin-ike serine proteases wasaso observed in an anaysis of the ESTs that accumu-

ated at the onset of contact between H. atroviridis andits funga prey species Thanatephorus cucumeris (ana-morph Rhizoctonia solani)and S. sclerotiorum20. Strainsoverexpressing one of these proteases (encoded by thegeneprb1) from H. atroviridis exhibited enhanced myco-parasitic activity22. The actions of any of these proteaseson the prey fungus may reease oigopeptides that maythen be bound by receptors on H. atroviridis which sensenitrogen starvation20. Such a mechanism woud be remi-niscent of that found in nematophagous fungi, in whichtrapping of the prey is induced by oigopeptides from thenematode23 (FIG. 2). It has been suggested that the cass IVG protein-coupled receptors (GPCRs) that are present

Box 1 | Nomenclature of the genus Hypocrea/Trichoderma

According to the International Code of Botanical Nomenclature (ICBN; article 59) 100, which also applies to fungi for

historical reasons, the teleomorph (sexual stage) name of a fungus should be used for species for which a complete

(holomorphic) life cycle has been described. The anamorph name should be used for confirmed agamospecies

(clonal species) or when no sexual stage is known. In this Review, when the whole genus of Trichoderma and

Hypocrea spp. is considered, the term Hypocrea/Trichoderma is applied; both teleomorph (Hypocrea) and anamorph

(Trichoderma) names are used at first mention for those species for which the complete life cycle is known, and only

the teleomorph name is used thereafter. We acknowledge that the modern trend is to abolish the use of the nameHypocrea in favour ofTrichoderma for the holomorph, and this practice will become valid after 1 January 2013

(according to the decision made at the International Botanical Congress in July 2011).

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Papilla-likestructure

Distressedhyphae

Proteases

Peptidesand smallmolecules

ROS and secondarymetabolites

Detoxification and stress response

Plant-pathogenic fungus

Hypocrea/Trichodermasp.Cell wall hydrolases andsecondary metabolites

G proteins

Gpr1 Nitrogen-sensingreceptor

Gene regulation

MAPK TFs

Healthy hypha

Figure 2 | Mycoparasitism ofHypocrea/Trichoderma spp. within the soil community.Hypocrea/Trichoderma spp.

recognize a plant-pathogenic fungus (a prey) via small molecules that are released by the pathogen; some of these

molecules may be peptides that are released by the action of proteases secreted by the Hypocrea/Trichoderma sp.

before contact. These molecules may bind to G protein-coupled receptors (such as Gpr1) or nitrogen-sensing receptors

on the surface of the Hypocrea/Trichoderma sp. hyphae, thereby eliciting a signalling cascade comprising G proteins

and mitogen-activated protein kinases (MAPKs), which may ultimately modulate the activities of as-yet-unknown

transcription factors (TFs). These factors then enhance the constitutive expression of genes that encode enzymes for

the biosynthesis of secondary metabolites and for cell wall lysis. Lectins from the pathogenic fungus and proteins

harbouring cellulose-binding modules from hyphae ofHypocrea/Trichoderma spp. may collaborate in the attachment

of the predator to the prey. At the same time, the plant-pathogenic prey responds by forming secondary metabolites

and reactive oxygen species (ROS) that elicit a stress response and detoxification in Hypocrea/Trichoderma spp.

Hemicellulolytic

Relating to the degradation

of plant hemicelluloses such

as xylans and pectins.

Nematophagous

Pertaining to fungi: specialized

in trapping and digesting

nematodes.

G protein-coupled receptors

(Guanine-nucleotide-binding

protein-coupled receptors).

Receptors that possess seven

transmembrane helices, bind

an extracellular signalling

molecule and transmit this

binding by activating a G

subunit.

in H. atroviridis 20 act as sensors for these oigopeptides13.H. atroviridis, H. virens and H. jecorina each have twoparaogues that are members of the cass IV GPCRs13.

There may be further GPCRs invoved in sensingthe prey. For exampe, Gpr1 (protein identificationnumber 160995 in the JGI T. atroviride v2.0 genomeof the Joint Genome Institute (JGI) Genome Porta),a member of the cycic AMP receptor-ike GPCRs, isrequired for mycoparasitism in H. atroviridis24. Furthersigna transduction from any of these receptors occurs

via a conserved G protein signaing cascade (FIG. 2) thatcomprises three G subunits, one G subunit and oneG subunit. H. atroviridis oss-of-function mutants forthe G subunit Tga1 dispayed a compete oss of myco-parasitic overgrowth on three hosts, a strong reductionof chitinase activities and decreased production of theantifunga compound 6-penty pyrone25,26. By contrast,the deetion oftgaA (a tga1 homoogue) in H. virensresuted in ony a somewhat reduced mycoparasiticactivity onAthelia rolfsii (anamorph Sclerotium rolfsii)27.

Mitogen-activated protein kinase (MAPK) pathways

represent one of the most prominent signa transduc-tion systems in fungi28. The Hypocrea/Trichoderma spp.

genomes harbour genes that encode three MAPKs: theso-caed pathogenicity MAPK (TmkA; aso known asTvk1 and Tmk1), the ce integrity kinase (TmkB) andthe osmoreguatory MAPK (Hog1)28. Deetion oftmkAin a P strain ofH. virens (P strains produce giovirinand are effective against Pythium spp.) resuted in a ossof antagonism against S. rolfsii but not R. solani 29,30. Bycontrast, deetion oftmkA in an H. virens Q strain (Qstrains secrete copious amounts of giotoxin and areeffective against R. solani) resuted in further improvedbiocontro against both R. solani and Pythium ultimum31.The different secondary metaboite profies of the P andQ strains may expain these different resuts, and morecompete information about the genome of P strainswi hep test this hypothesis. The deetion of the tmk1homoogue in H. atroviridis resuted in reduced myco-parasitism against R. solani and increased production ofchitinase and antifunga compounds32. The roes of theother two MAPKs, TmkB and Hog1, are ess we under-stood because mutants for these genes are characterizedby poor growth, which precudes successfu antagonism.

For exampe, H. virens mutants for TmkB were defective inmycoparasitism on S. rolfsii33, and H. atroviridis mutants

R E V I E W S


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a b

c d

e f

Dead hypha ofNeurospora crassa

N. crassa

N. crassa

Hypocrea atroviridis

H. atroviridis

H. atroviridis

Figure 3 | Mycotrophy ofHypocrea atroviridis/Trichoderma atroviridae.

a,b | Hypocrea atroviridis/Trichoderma atroviridae grows around, enwraps and attachesto a dead hyphal fragment of the fungus Neurospora crassa (part a is a brightfield

image, and part b is a confocal image). The membrane-sensitive red dye FM4-64 stains

the membranes of intact hyphae and the complete hyphal compartment of dead

hyphal fragments (because the cell wall and the plasma membrane are then

permeable). The scale bars represent 20m. c | Attachment ofH. atroviridis to anN. crassa strain that expressed cytosolic GFP, showing the formation of papilla-like

structures (arrow). Membranes were stained with FM4-64. The scale bar represents

20m. d | An H. atroviridis hypha grows towards and around an N. crassa hypha.Membranes were stained with FM4-64, and an N. crassa strain expressing both

cytosolic GFP and nucleus-specific histone H1GFP was used. The scale bar represents

10m. e,f| Brightfield differential interference contrast images ofH. atroviridisgrowing in coils around its own hyphae. The scale bars represent 50 m. Imagescourtesy of N. D. Read (University of Edinburgh, UK), V.S.-S. and C.P.K.

Lectins

Sugar-binding proteins that

are highly specific for the

respective sugar moiety and

have a role in the recognition

of cells and proteins.

for Hog1 (a protein which is invoved in toerance toosmotic and oxidative stress) showed no mycoparasiticabiity34.

Attachment to the prey hypha. Athough mycotrophyrequires ony an attachment to the funga substrate,mycoparasitism typicay requires coiing around

the prey myceium and formation of heix-shapedhyphae17,18, and this phenomenon is dependent on therecognition oflectins from the funga prey35(FIGS 2,3).However, pant ectins induce coiing to a simiar extent,suggesting that ectins are not determinants of specificityin the attachment ofHypocrea/Trichoderma spp. to theirprey species25. Furthermore, coiing is not stringentycorreated with mycoparasitism, as hyphae of someHypocrea/Trichoderma spp. can coi around themsevesin the absence of prey36. Indeed, spira or heica hyphaeongations are diagnostic characteristics for many spe-cies, for exampe Trichoderma spirale and Trichodermahelicum (see Trichoderma Onine).

Mycoparasitic attack byHypocrea/Trichoderma spp.is often proceded by their growth aongside the hosthyphae and by their formation of papia-ike structures(FIG. 3), events that are independent of the prey spe-cies25,37. Degradation of the ce wa and penetration ofthe umen occur at points where papia-ike structuresare formed17,18,37. These structures are simiar to thoseinduced in T. cf. harzianum by tomato (Solanum lyco-

persicum)37 and anaogous to the appressorium of pant-pathogenic fungi. In the rice bast fungusMagnaporthegrisea, gycero that is generated from storage ipidsserves to buid up the turgor needed for the mechanicapressure that enabes penetration of the pant ce wa38.The papia-ike structures ofHypocrea/Trichoderma spp.may aso buid up gycero for a simiar purpose, as thetranscription of genes invoved in ipid cataboism andosmoreguation increases during the contact stage ofmycoparasitism in H. atroviridis20.

Contact with and binding to a potentia prey is notrestricted to parasite hyphae: spores ofH. atroviridisadhere to the hyphae ofP. ultimum before germinatingon them36. The mechanism of conidia affinity for thehost myceium is unknown but coud invove hydro-phobins; these are sma amphiphiic proteins contain-ing eight cysteine residues, and Hypocrea/Trichodermaspp. have the highest number of these proteins amongthe ascomycetes (as deduced from genomic sequences)39.

Defence responses ofHypocrea/Trichoderma spp.Another event that is common to Hypocrea/Trichodermaspp. is the induction of genes for the heat shock response,the oxidative stress response and detoxification pro-cesses (such as those encoding ABC effux transportersand the peiotropic and mutidrug resistance transport-ers) in the presence of the prey19,20(FIG. 2). The funga

preyR. solani uses radica oxygen species as signaingmoecues during scerotia formation40 and excretesantifunga metaboites41, and both radica oxygen spe-cies and antifunga metaboites may eicit the stressresponse that is observed in Hypocrea/Trichoderma spp.An H. atroviridis knockout for one of the genes encodingan ABC transporter (Abc2) resuted in decreased biocon-tro ofR. solani, thus providing support for the roe ofdetoxification in mycoparasitism42.

Killing the prey. The fina death of the prey resutsfrom the synergistic actions of antifunga secondarymetaboites (BOX 2) and ce wa-hydroytic enzymes

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Appressorium

A flattened hyphal pressing

structure from which an

infection peg emerges that

enters the host.

Predation

An inter-organism association

in which one organism affects

another adversely and itself

benefits from the interaction.

A predator ultimately kills its

prey and consumes all or part

of the prey organism.

that are secreted by Hypocrea/Trichoderma spp.The importance of these moecues to the ifestyeof the mycoparasites is refected in the Hypocrea/Trichoderma spp. genomes, which contain a argenumber of genes encoding enzymes for the synthesisof these moecues13. As an exampe, H. virens has theargest number (28) of nonribosoma-peptide syn-thetases known for any fungus. In addition, orthoo-gous genes that are shared between H. atroviridis andH. virens (but are not present in H. jecorina) seem toencode proteins for the synthesis of secondary metabo-ites13 and may thus represent the machinery for thesynthesis of as-yet-unknown antifunga compounds.

The ce wa accounts for approximatey 30% of thedry weight of the funga ce and consists mainy of chi-tin, -1,3-gucans, -1,3-gucans and -1,4-gucans43.Interestingy, H. atroviridis and H. virens have manychitinases (29 and 36, respectivey)13,44. Enhancing chi-tinase activity by adding a ceuose-binding modue tothe chitinases Chit33 and Chit42 increased the myco-parasitic abiity ofT. cf. harzianum45. The addition of

ceuose-binding modues enabed these chitinases tobind more tighty to insoube chitin substrates. Somechitinases from Hypocrea/Trichoderma spp. have evovedunder positive seection46, which is typica of a co-evoutionary arms race between host and pathogen.However, the deetion of certain chitinase genes in someHypocrea/Trichoderma spp. did not resut in the oss ofmycoparasitism or biocontro abiities15,18, probabybecause of gene redundancy. Hypocrea/Trichoderma spp.

aso contain an expanded set of chitosanases of theGH famiy 75; these proteins hydroyse chitosan, apartiay deacetyated form of chitin13.

The second most abundant poymer in funga cewas is -1,3-gucan43 with -1,6-branches, which ishydroysed by -1,3-gucanases; genes encoding thistype of enzyme seem to be over-represented in thegenomes ofHypocrea/Trichoderma spp. when com-pared with the genomes of other reated fungi13.-1,6-gucanases have been detected in the area ofinteraction between Hypocrea/Trichoderma spp. andtheir prey species. Overexpression of the -1,6-gucanaseBgn16.3 in T. cf. harzianum CECT 2413 resuted in amore efficient biocontro strain for inhibition of thegrowth ofB. cinerea, R. solani and Phytophthora citroph-thora47. In addition, T. cf. harzianum andH. virens strainsoverproducing -1,6-gucanases exhibited more efficientbiocontro ofR. solani, B. cinerea46 and P. ultimum48.

Animals as targets of an opportunistSome of the traits that seem to have evoved in Hypocrea/

Trichoderma spp. in reation to mycotrophy may havefunctioned as pre-adaptations to aow parasitism orpredation on animas. For exampe, severa Hypocrea/Trichoderma spp. successfuy antagonize and ki pant-parasitic nematodes that occur in the rhizosphere49.Commerciay reevant nematode pests in agricuture,such as the root-knot nematodes (Meloidogyne spp.) andthe cyst nematodes (Heterodera spp. and Globodera spp.),cannot be controed by crop rotation owing to theirbroad host range49. However, it is remarkabe that differ-ent Hypocrea/Trichoderma spp. such as T. cf. harzianumcan protect pants against the attack ofMeloidogyneincognita by coonizing the eggs and second-stage juvenies of the nematode49. This parasitism ofnematode eggs requires penetration of the eggshe,which is formed by severa ayers (incuding a thick chi-tinous ayer) that are considered to be a major barrierfor infection50. Thus, the rich arsena of chitinases inHypocrea/Trichoderma spp. may provide an advantagefor opportunistic nematophagy. In addition, the highnumber of subtiisin-ike S8 proteases in Hypocrea/Trichoderma spp. may be important for penetration ofthe adut nematode cutice, which is composed of coa-gen-ike and keratin-ike proteins (FIG. 4). Subtiisins andchemotrypsins have been coned from severa Hypocrea/Trichoderma spp.5153, and the H. atroviridis akaine sub-tiisin Prb1 and the T. cf. harzianum chemotrypsin-ike

protease Pra1, which both have important roes in myco-parasitism20,50, aso contribute to the abiity of the fungito penetrate nematode eggs51,52.

Some Hypocrea/Trichoderma spp. can cause invasivemycoses inmammas, incuding immunocompromisedhumans54. Athough these fungi are not a major threatto humans, they nevertheess pose therapeutic cha-enges because of their resistance to most antifungaagents55. This remarkabe resistance may be the resut ofthe adaptation ofHypocrea/Trichoderma spp. to combatthe defence metaboites that are produced by prey fungi.To date, ony two cosey reated species, T. longibrachia-tum and Hypocrea orientalis, have been shown to infect

Box 2 | Secondary metabolites produced by Hypocrea/Trichoderma spp.

Nonribosomal peptides

Nonribosomal peptides are synthesized by large modular enzymes that are known

as nonribosomal peptide synthetases (NRPSs). Peptaibols are 1125 amino acid

linear nonribosomal peptides that are rich in aminoisobutyric acid and bear anacetylated amino terminus and a carboxyterminal amino alcohol101. They are

amphipathic in nature and have antibiotic properties because of their ability to

selfassemble and to form voltagedependent ion channels in membranes. They

act synergistically with cell wall hydrolases to antagonize other fungi by

preventing resynthesis of the cell wall, and thus potentially have a role in

mycotrophy102. Another nonribosomal peptide, gliotoxin, is produced by Hypocrea

virens/Trichoderma virens Q strains, which give very effective disease control of

cotton seedling disease103,104. However, there are contradictory reports on the role

of gliotoxin in mycotrophy under controlled conditions105107.

PolyketidesPolyketides are synthesized by polyketide synthases (PKSs). There are several

NRPSPKS hybrid enzymes encoded in the genomes ofHypocrea atroviridis/

Trichoderma atroviride, Hypocrea jecorina/Trichoderma reesei and H. virens13

,but their roles remain unknown.

Isoprenoid-derived metabolites

H. virens produces the fungistatic and anticancer steroid viridin, which can be

reduced to viridiol, a compound with herbicidal properties108. A gene cluster that

is putatively involved in viridin biosynthesis has been identified in H. virens109. In

addition, Trichoderma arundinaceum and Trichoderma brevicompactum produce

the trichothecenes harzianum A and trichodermin, respectively, the latter being

highly fungitoxic and phytotoxic and formed by a cascade of reactions in which

trichodiene synthase (Tri5) catalyses the first step 110.

Pyrones6pentyl2Hpyran2one (6PP) is a volatile component (with a coconut aroma)

that has antifungal activity and is produced by H. atroviridis111.

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Hypocrea/Trichoderma sp.

Detoxification

Ethylene

IAA Nitrilase

Xylanases

AAC deaminase

Proteases

Peptaibols

Cerato-plataninsand otherSSCPs

Hydrophobinsand swollenin

Growthstimulation

Soil nematode

Sucrose

Plant root

Inducedsystemic

resistance

Mucigel

Hydroxyperoxidelyase, peroxidaseand phenylalanineammonia lyase

Soil-borne plant-pathogenic fungus

Figure 4 | Interactions ofHypocrea/Trichoderma spp. with other organisms in the

rhizosphere. Hyphae ofHypocrea/Trichoderma spp. release several components that

trigger systemic resistance in the plant. Only the effects that occur in the rhizosphere

and are triggered by a known Hypocrea/Trichoderma spp. component are shown (for

an update on further positive effects, such as resistance to abiotic plant stresses,

enhancement of photosynthetic efficiency and improved nitrogen usage, see REF. 71).

Peptaibols and the cerato-platanin Sm1 (also known as Epl1 in some species) induce a

systemic resistance in the plants, culminating in the synthesis of plant hydroperoxidelyase, peroxidase and phenylalanine ammonia lyase (which induces lignification).

Furthermore, the xylanase Eix elicits plant defence responses, probably acting as a

microorganism-associated molecular pattern. The 1-aminocyclopropane-1-carboxylic-

acid (AAC) deaminase inhibits ethylene formation by the plant, and this leads to

enhanced root growth; a constitutively secreted nitrilase might aid in the formation of

the auxin 3-indole acetic acid (IAA). Attachment ofHypocrea/Trichoderma spp. to the

plant roots requires hydrophobins and swollenin. Finally,Hypocrea/Trichodermaspp.

benefit from the plant roots by receiving sucrose as a carbon source, enabling faster

fungal growth. The nematophagy ofHypocrea/Trichoderma spp. probably involves

chitinases and subtilisin-like S8 proteases. SSCPs, small secreted cysteine-rich proteins.

Mycoses

Fungal infections of animals

or humans.

Mycorrhizal fungi

A group of fungi that establish

symbiotic or weakly parasitic

associations with the roots of

vascular plants.

immunocompromised patients7. However, it shoud be

noted that whereas T.longibrachiatum is essentiay cona,H. orientalis forms a wordwide recombining popua-tion8; this may be reevant for antifunga therapy, as genesencoding factors for antibiotic resistance and viruencecoud be exchanged during sexua reproduction in H. ori-entalis. Cinica isoates of both species have identica hap-otypes to common environmenta strains, indicating thatthere is a threat of nosocomia infections, as virtuay anystrain of these species coud cause invasive mycoses.

There have been few attempts towards an under-standing of the mechanisms by which particuar mem-bers of the Hypocrea/Trichoderma genusinfect humances. A the infecting species can grow at 37 C, but not

a Hypocrea/Trichoderma strains that can grow at 37 Care opportunistic human pathogens. When T. longibra-chiatum is incubated with ung ce cutures, the humances rapidy start to sediment and ose their adhesiveproperties, suggesting that proteases and/or secondarymetaboites from the fungus are acting on these ces. Nosuch effect was observed for H. jecorina, which was usedas a non-pathogenic contro56.

In the rhizosphere

Why the rhizosphere?The rhizosphere is among the com-mon ecoogica niches for Hypocrea/Trichoderma spp.and provides opportunities for both biotrophy and sapro-trophy on pant root exudates. This is iustrated by thefact that the highest species richness of this funga genusin a singe habitat has been found in the rhizosphere ofthe coffee pant Coffea arabica in Ethiopian highand for-ests57; by contrast, a simiar survey in non-rhizospheresoi on Sardinia (Itay) showed remarkaby poor diver-sity58. The affinity ofHypocrea/Trichoderma spp. for therhizosphere can be expained by two of their nutritiona

preferences. First, the roots of 92% of and pants arecoonized bymycorrhizal fungi that are potentia preyfor a mycotroph. However, the interactions betweenmycorrhiza fungi and Hypocrea/Trichoderma spp. aresti poory understood5964: whereas some studies sug-gest a synergism between the two types of fungi, othershave observed that Hypocrea/Trichoderma spp. attackarbuscuar mycorrhiza fungi and suppress their coo-nization of pant roots. Moreover, a reduction in thepopuation density ofHypocrea/Trichoderma spp. dueto arbuscuar mycorrhiza fungi has been noted64. Fewstudies have focused on the interaction ofHypocrea/Trichoderma spp. with ectomycorrhiza fungi65. Second,the pant roots, and especiay the root tips, are coveredby a ge-ike simy capsue (caed the mucige) com-posed of highy hydrated poysaccharides such as pectinsand hemiceuoses (particuary rhamnogaacturo-nans and arabinoxyans) that are secreted from theoutermost ces of the root cap. These componentsare easiy degradabe targets for the hemiceuases ofHypocrea/Trichoderma spp., which may have evovedfor the utiization of poysaccharides that are reeasedfrom pre-degraded wood by potentia funga prey.Indeed, successfu estabishment ofT. cf. harzianumCECT 2413 in the tomato rhizosphere requires anendopoygaacturonase66.

Monosaccharides and disaccharides excreted by pant

roots into the rhizosphere provide an important carbonsubstrate for mycorrhizae67, and sucrose has a simiar roefor theestabishment ofH. virens in the rhizosphere68.As the genomes ofH. atroviridis, H. virens and H. jeco-rina contain genes encoding intraceuar (but not extra-ceuar) invertases, sucrose must be taken up by a sucrosepermease before being hydroysed. H. virens contains ahighy specific sucrose transporter that is induced inthe eary stages of root coonization and has biochemi-ca properties that are simiar to pant sucrose carriers69,suggesting that sucrose is activey transfered from pantto fungus. In addition, the genomes ofH. atroviridisand H. virens encode a arge number of major faciitator

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Induced systemic resistance

A process by which plants

respond to a non-pathogenic

microorganism, with a

signalling cascade that is

dependent on jasmonate and

ethylene. This response leads

to a long-lasting ability to

mount a faster and stronger

broad-spectrum defence when

challenged by a pathogen.

Both pathogen-associated

molecular pattern-triggered

immunity and

effector-triggered immunity

can lead to induced systemic

resistance.

Ethylene

A gaseous, unsaturated

hydrocarbon that acts as a

plant hormone to promote

growth and development and

as an inhibiting stress factor.

Callose

A -1,3-linked polysaccharide

of the plant cell wall; this

polysaccharide is formed in

response to wounding

(including infections by

pathogens).

Systemic acquired

resistance

A plant defence mechanism

that is usually induced by

exposure to a pathogen and

confers long-lasting protection

against a broad spectrum of

microorganisms. It involves the

production of the signal

molecule salicylic acid, which

then leads to the accumulation

of pathogenesis-related

proteins that are thought to

contribute to resistance.

soute transporters13, the roes for which in the acquisi-tion of other root exudates remain unknown. In sum-mary, the presence of funga prey and the avaiabiity ofroot-derived nutrients may have been major attractors forthe ancestors ofHypocrea/Trichoderma spp. to estabishthemseves in the rhizosphere and to deveop interactionswith pant roots.

Dialogue with the plant. Like fungi and animas, pantsrespond to the presence of other organisms by activat-ing potentia defence mechanisms. This is best under-stood for various pant-pathogenic species that eicita two-branched innate immune defence 70. The firststage generay recognizes and responds to pathogen-associated moecuar patterns (PAMPs) or micro-organism-associated moecuar patterns (MAMPs) moecues that are commony found in microorgan-isms and is known as PAMP-triggered immunity(PTI), whereas the second stage responds to viru-ence factors from the pathogen and is caed effector-triggered immunity (ETI). As do other microorganisms

that are not pant pathogens, Hypocrea/Trichoderma spp. trigger induced systemic resistance (ISR) (FIG. 4),which cuminates inthe accumuation of componentsof the associated jasmonate and ethylene signaingpathways, such as hydroperoxide yase, peroxidaseand phenyaanine ammonia yase (which induces ig-nification)71. For exampe, the action of funga endo-pectinases on the mucige reeases oigogaacturonidesthat activate pant defence mechanisms66. As a resut ofrecognizing MAMPs and/or moecues reeased duringthe initia stages of the interaction, the pant depositsmore callose and ceuose in its ce was and reeasesphenoic compounds, both of which actions prevent fur-ther coonization, as observed during the eary stagesof root coonization by T. asperelloides on Cucumissativus (cucumber)72,73. As Hypocrea/Trichoderma spp.are not pant pathogens, they are not expected to eicitthe second stage of the pant innate immune response.However, systemic acquired resistance (SAR), normayassociated with the second stage of the pant immuneresponse, is induced by T. asperellum in cucumberpants in a concentration-dependent manner and mayoccur in the eary stages of the funga interactions withroots73. It must be noted that these effects have beenstudied in ony a fewHypocrea/Trichoderma species andstrains that are particuary effective in the stimuationof pant defences, nameyT. asperelloides T203 (formery

cassified as T.asperellum T203), H. virens and theprotopast fusion hybrid T. harzianumT-22.

Severa casses of moecues from Hypocrea/Trichoderma spp., such as xyanases, peptaibos, swo-enin and cerato-patanins, act as MAMPs (FIG. 4). Theendoxyanase Eix (aso known as Xyn2) from T. virideATCC 52438 was the first Hypocrea/Trichoderma spp.protein known to eicit ethyene formation in tobacco(Nicotiana tabacum) and tomato74. Unfortunatey, thespecies identity of this strain has never been re-assessedby moecuar methods and thus must be considered asuncertain. An effective biocontro strain ofH. virenssecretes an endoxyanase that is identica to Eix 75, and

genes encoding homoogous enzymes are found in thegenomes ofH. jecorina (protein identifier 123818 in theJGI T. reesei v2.0 genome) and H. virens (protein identi-fier 72838 in the JGI T. virens Gv29-8 v2.0 genome).Remarkaby, the cataytic activity of Eix is not requiredfor eiciting the pant defence responses76,77; thus, theenzyme itsef, and not its reaction product, must beacting as a MAMP. In fact, to eicit the pant response,Eix binds to pant Eix receptor 2 (Eix2; aso known asLeEix), a member of a superfamiy of pant eucine-richrepeat receptor-ike proteins that aso carry a signa forreceptor-mediated endocytosis, which is essentia for theproper induction of defence responses78,79. In addition,binding of Eix to the pant receptors causes aterationsin membrane function that are required for eiciting thepant defence response80.

Bocking the synthesis of peptaibos (a group of non-ribosoma peptides; see BOX 2) inH. virens by disruptingthe gene encoding the peptaibo synthase Tex1 resuts instrains that do not induce ISR in cucumber, athough thiscan be overcome by the addition of peptaibo mixtures81.

The mechanism by which peptaibos induce ISR is notknown but may be reated to the abiity of these peptidesto ater membrane function, as described for Eix (REF. 80).

Swoenin is a protein that carries a ceuose-bindingmodue and can disrupt the crystaine ceuose struc-ture of pant ce was82. It contributes to root cooniza-tion in T. asperellum and induces oca defence responsesbut not ISR83. Swoenin has sequence simiarity toexpansins, which are pant proteins that faciitate expan-sion of the pant ce wa in roots and root hairs84, andHypocrea/Trichoderma spp. may take advantage of aswoenin-induced increase in root surface area whenestabishing themseves in the pant rhizosphere.

Cerato-patanins are sma secreted proteins that arecharacterized by four cysteines which form two disu-phide bonds. The H. virens cerato-patanin Sm1(asoknown as Ep1) induces ISR in maize (Zea mays) and cot-ton (Gossypiumhirsutum)85, and the orthoogue of Sm1in H. atroviridis (Ep1)is one of the major proteins thatis constitutivey secreted by the fungus86. Gycosyationof Sm1 maintains the protein in a monomeric form,which eicits ISR87. Degycosyation eads to the forma-tion of an Sm1 dimer, which does not eicit ISR. It hasbeen suggested that the pant may ater the aggregationstate of Sm1 by degycosyation and utimatey affect itsabiity to induce defence responses. H. jecorina, H. virensand H. atroviridis have three paraogues ofsm1 each,

whereas most other fungi from reated genera have onyone, suggesting that cerato-patanins may be importantfor Hypocrea/Trichoderma spp. Other sma secretedcysteine-rich proteins are encoded in the Hypocrea/Trichoderma spp.genomes13 and may have a roe inroot coonization, simiar to that described for the smasecreted proteins of the ectomycorrhiza basidiomyceteLaccaria bicolor, which accumuate in the hyphae thatcoonize the pant root88.

Promotion of plant growth. At east in some cases, theassociation ofHypocrea/Trichoderma spp. with rootscan promote pant growth (FIG. 4). For exampe, H. virens

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increases the root system biomass and the atera-rootgrowth rate ofArabidopsis thaliana. Auxin-mediatedresponse pathways may have a roe in mediating theseeffects, as pant mutants with defects in these pathwaysshow reduced effects ofHypocrea/Trichoderma spp.associations89. However, the promotion of pant growthmay aso be mediated by a decrease in the eves ofthe pant hormone ethyene90. T. asperelloides T203possesses an -1-aminocycopropane-1-carboxyate(ACC) deaminase gene (acc1) that encodes an enzymewhich ceaves ACC, a key intermediate in ethyene bio-synthesis, andis expressed during the interaction withroots ofBrassica napus (oiseed rape)91. A knockout forthis gene reduced the abiity of the fungus to promoteroot eongation. Because a sustained high eve of ethy-ene inhibits root eongation, the Acc1 enzyme provides amechanism for faciitating the formation of onger roots.Simiar enzymes have been described in bacteria thatpromote pant growth92.

In addition, the Hypocrea/Trichoderma spp. genomescontain many genes that encode nitriases, as compared

with other ascomycetes13. These nitriases may have aroe either in hydroysing -cyano-l-aanine, a metaboitewhich is formed from cyanide reeased during the fina stepof ethyene biosynthesis, or in converting the pant metabo-ite indoe-3-acetonitrie to indoe-3-acetic acid (IAA), ahormone that promotes the growth of pant roots93.

EndophytismEndophytic biotrophy (that is, symptomess growthinside pant tissue) is common among bacteria and fungi.These microorganisms offer a wide range of benefits tothe host, incuding stimuation of pant growth, a deayto the onset of drought stress and the prevention of attacksby pathogens94. Ony a fewHypocrea/Trichoderma spp.

have been isoated as endophytes (TABLE 1), athough itis ikey that many other species can behave as facuta-tive endophytes. Amost a the isoated endophyteshave been cassified as new taxa and with the excep-tion ofHypocrea koningiopsis/Trichoderma koningiopsis,Hypocrea stilbohypoxyli/Trichoderma stilbohypoxyliand Hypocrea stromatica/Trichoderma stromaticum have no known teeomorphs. A phyogenetic anaysispaces them in a termina position within their cades,suggesting that the deveopment of endophytism inthe genus Hypocrea/Trichoderma was evoutionariyrecent9597. Some species, such as Trichoderma hamatum,are detected both as endophytes and as common inhabit-ants of the soi and the rhizosphere, and such a character-istic is known for many other opportunistic funga generaas we98. It is therefore uncear whether any obigate endo-phytic Hypocrea/Trichoderma spp. exist. Interestingy, themyceium of arbuscuar mycorrhizae on the outer side ofthe coonized roots of potato (Solanum tuberosum) can beused byHypocrea/Trichoderma spp. to enter into the pantroots99, which suggests that traits reated to mycotrophy

faciitate the evoution of endophytism. No genomesfrom Hypocrea/Trichoderma strains that were isoated asendophytes have yet been sequenced.

ConclusionsThe recent advent of genomic and transcriptomic data,combined with insights into the moecuar ecoogy andpopuation genetics ofHypocrea/Trichoderma spp., hasprovided a weath of information that aows a deeperunderstanding of this important funga genus.

Unti recenty, it was commony thought that mostTrichoderma spp. were asexua soi fungi. This was inpart due to difficuties in mating these organisms underaboratory conditions. However, the appication ofpopuation genetics has now shown that many of theseTrichoderma spp. that were previousy beieved to beasexua in fact dispay an evoutionary history of sexuarecombination, and ony four have been proved to becona (stricty asexua)58. These concusions are asorefected in the resuts from diversity surveys on thegenus Hypocrea/Trichoderma, which showed that, outof ~150 species characterized by genetic markers, themain fraction comprises hoomorphic species that growon decaying wood or on basidiomycetes3,4. Mycotrophyis thus widespread within the genus.

Comparative anaysis of the genomes from H. jecorina,H. virens and H. atroviridis further expanded this finding

to concude that mycotrophy is in fact a very ancient trait ofthe genus: a phyogenetic anaysis of 100 orthoogues andsyntenic proteins from the three species (rooted against thereated genera Chaetomium and Gibberella) and a genusphyogeny based on the nuceotide sequence of the geneencoding the RNA poymerase -subunit reveaed thatH. atroviridis has an ancestra position within the genus13.However, the gene inventory ofH. atroviridis incudes sev-era ampified gene famiies with roes in competition andantagonism13, thus indicating a genetic predisposition ofthe species for mycotrophy.

A these data suggest that mycotrophy is a basic prop-erty of the genus Hypocrea/Trichoderma and sti the

Table 1 | Endophytic Hypocrea/Trichoderma spp.

Species Putativelyobligate?

Host plant Location

Trichodermaamazonicum95 Yes Hevea spp. Peru

Trichodermacaribbaeum var.aequatoriale96

Yes Theobroma spp. Tropical America

Trichodermaevansii97 Yes Lophira alata Cameroun

Cola verticillata Cameroun

Theobroma gileri Peru

Trichodermahamatum94 No Theobroma cacao Ecuador

Hypocrea koningiopsis/Trichoderma koningiopsis96

No Theobroma spp. Not available

Trichodermamartiale112 Yes T. cacao Brazil

Trichodermaovalisporum96 Yes Banisteriopsis caarpi Ecuador

Trichodermapaucisporum113 Yes T. cacao Ecuador

Trichodermascalesiae114 Yes Scalesia pedunculata GalapagosIslands

Hypocrea stilbohypoxyli/Trichoderma stilbohypoxyli96

No Fagus spp. United Kingdom

Trichodermataxi115 Yes Taxus mairei China

Trichodermatheobromicola113 Yes T. cacao Peru

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major ifestye for many of its species. However, severaspecies seem to have evoved further towards new eco-ogica niches or to have deveoped specia traits, probabyfaciitated by the presence of genes that enabe effectivecompetition and opportunism13. For exampe, T. longi-brachiatum can coonize immunocompromised humans,H. jecorina speciaizes on coonizing dead wood, andother species have so far been isoated ony as endophytes;a these species occupy termina positions in the phyo-genetic trees6,7,9597, which suggests that they are the mostrecent taxa of the genus.

The presence of potentia funga prey and pant root-derived nutrients in the rhizosphere may have attractedHypocrea/Trichoderma spp. ancestors towards cooniz-ing pant roots. Moreover, mycotrophy-reated traits(such as the presence of certain proteases, chitinases andsecondary metaboites) may have faciitated the evou-tion of further positive interactions between Hypocrea/Trichoderma spp. and pants. We shoud note, however,that no known components or mechanisms depoyed by

Hypocrea/Trichoderma strains seem to have evoved spe-cificay for this process, as most of these components areinvoved in other ceuar functions (such as nutrition orcompetition) or have orthoogues in other fungi that havenot been described as taking part in communication withthe pant13. Further studies of the interactions betweenpants, the rhizosphere, mycorrhizae and Hypocrea/Trichoderma spp. are needed for a better understandingof these processes.

Finay, arge-scae genome-sequencing projects ofadditiona Hypocrea/Trichoderma spp. (such as T. harzi-anum, T. asperellum andT. longibrachiatum) are currentybeing undertaken by the US Department of EnergysJGI Funga Genetics Program and wi enabe a morecomprehensive moecuar-eve anaysis of the ecoogicadiversity of the genus. This wi not ony hep us to under-stand the moecuar basis of the opportunistic nature andenvironmenta successes ofHypocrea/Trichoderma spp.but aso improve the use of these fungi in biotechnoogy,agricuture and other areas.

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AcknowledgmentsWork in the C.P.K., I.S.D., V.S.-S. and S.Z. laboratory (headed

by C.P.K.) was supported by grants from the Austrian Science

Foundation (P17895-B06, P20559, T390 and P-19340) and

the Vienna Science and Technology Fund (WWTF LS09-036).

The work of B.A.H., C.M.K. and P.K.M. was supported in part

by grant TB-8031-08 from the Texas Department of

Agriculture, USA, and the USIsrael Binational Agricultural

Research and Development Fund.

Competing interests statementThe authors declare no competing financial interests.

FURTHER INFORMATIONChristian P. Kubiceks homepage:

http://www.vt.tuwien.ac.at/molbio/

International Subcommission on TrichodermaandHypocrea

Taxonomy (ICTF): http://www.isth.info/

JGI Fungal Genetics Program:

http://genome.jgi-psf.org/programs/fungi/index.jsf

JGI Genome Portal: http://genome.jgi-psf.org/

JGI genome T. atroviride v2.0:

http://genome.jgi-psf.org/Triat2/Triat2.home.html

JGI genome T. reesei v2.0:

http://genome.jgi-psf.org/Trire2/Trire2.home.html

JGI genome T. virens Gv298 v2.0:http://genome.jgi-psf.org/

TriviGv29_8_2/TriviGv29_8_2.home.html

Trichoderma Online:http://nt.ars-grin.gov/taxadescriptions/

keys/TrichodermaIndex.cfm

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