Fmicb 10 01030

REVIEW
published: 15 May 2019

doi: 10.3389/fmicb.2019.01030
Trichoderma as a Model to Study

Effector-Like Molecules
Claudia A. Ramírez-Valdespino 1,2 , Sergio Casas-Flores 3 and Vianey Olmedo-Monfil 1*
1
División de Ciencias Naturales y Exactas, Departamento de Biología, Universidad de Guanajuato, Guanajuato, Mexico,
2
Laboratorio de Biohidrometalurgia, Departamento de Medio Ambiente y Energía, Centro de Investigación en Materiales
Avanzados, Chihuahua, Mexico, 3 Laboratorio de Genómica Funcional y Comparativa, División de Biología Molecular,
Instituto Potosino de Investigación Científica y Tecnológica, San Luis Potosí, Mexico
Plants are capable of perceiving microorganisms by coordinating processes to establish

different forms of plant–microbe relationships. Plant colonization is governed in fungal
and bacterial systems by secreted effector molecules, suppressing plant defense
responses and modulating plant physiology to promote either virulence or compatibility.
Proteins, secondary metabolites, and small RNAs have been described as effector
molecules that use different mechanisms to establish the interaction. Effector molecules
have been studied in more detail due to their involvement in harmful interactions, leading
to a negative impact on agriculture. Recently, research groups have started to study the
effectors in symbiotic interactions. Interestingly, most symbiotic effectors are members
of the same families present in phytopathogens. Nevertheless, the quantity and ratio of
Edited by:
secreted effectors depends on the microorganism and the host, suggesting a complex
Sabrina Sarrocco,
University of Pisa, Italy mechanism of recognition between the plant and their associated microorganisms.
Reviewed by: Fungi belonging to Trichoderma genus interact with plants by inducing their defense
Paul Dean, system and promoting plant growth. Research suggests that some of these effects
Teesside University, United Kingdom
Francesco Vinale,
are associated with effector molecules that Trichoderma delivers during the association
Istituto per la Protezione Sostenibile with the plant. In this review, we will focus on the main findings concerning the effector
delle Piante (CNR), Italy
molecules reported in Trichoderma spp. and their role during the interaction with plants,
*Correspondence:
mainly in the molecular dialogue that takes place between them.
Vianey Olmedo-Monfil
vg.olmedo@ugto.mx Keywords: Trichoderma, effector molecules, plant–microbe interactions, secondary metabolites, effector
proteins, small RNA
Specialty section:
This article was submitted to
Plant Microbe Interactions, INTRODUCTION
a section of the journal
Frontiers in Microbiology
One of the main challenges that agriculture production encounters today is to supply the demands
Received: 30 November 2018 of quality and quantity for the producer and consumer without affecting the environment. Various
Accepted: 24 April 2019
pathogenic agents attack the crops, among which filamentous fungi are the most destructive,
Published: 15 May 2019
causing important economic losses (Singh, 2014). To implement strategies to control plant diseases,
Citation: it is necessary to understand the pathogenic process, determining how these fungi are established in
Ramírez-Valdespino CA,
plants and how they generate tissue damage and bypass plant defenses. In this sense, one of the main
Casas-Flores S and Olmedo-Monfil V
(2019) Trichoderma as a Model
events currently under scrutiny corresponds to the early stages of the pathogen–plant interaction.
to Study Effector-Like Molecules. Now it is known that successful pathogens deliver a wide range of molecules to the plant, which
Front. Microbiol. 10:1030. allows them to overcome the obstacles presented by the plant, regarding perception, signaling,
doi: 10.3389/fmicb.2019.01030 or active defense response (Di et al., 2016; Shen et al., 2018). Also, there is ambiguity about the
Frontiers in Microbiology | www.frontiersin.org 1 May 2019 | Volume 10 | Article 1030

Ramírez-Valdespino et al. Trichoderma Effectors
classification of the molecules released by the pathogens, (ET). In this layer of defense, PDF1.2 (Plant defensin 1.2),
depending on the degree of response generated by the plant Thi2.1 (Thionin) or Chib (Chitinase B) are commonly used
immune system and their impact on the pathogenic process as marker genes (Van Loon et al., 2006). Also, the systemic
(Thomma et al., 2011). Initially, the gene-for-gene model acquired resistance (SAR), regulated by salicylic acid (SA),
proposed that the interaction of an avirulent protein (Avr) leads to the expression of Pathogenesis-Related genes (PR)
from the pathogen with a plant counterpart, a resistant plant (Bari and Jones, 2009). Pathogens suppress the PTI producing
protein (R), triggers the plant defense response, avoiding a wide number of effectors with different functions, such as
disease progression. However, it has been determined that this the prevention of the plant recognition or in the formation of
interaction could also lead to the pathogenic processes, so it infective structures (Kulkarni et al., 2005; de Jonge et al., 2010).
was redefined that avirulence factors can also be virulence Traditionally, agriculture techniques to counteract
factors (Flor, 1942; Bent and Mackey, 2007; Boller and Felix, phytopathogens involve the use of chemical formulations
2009). For these pathogen-derived molecules, the term “effector” that have secondary effects such as toxicity and soil pollution.
was proposed, defined as any given molecule that can alter Safer agricultural strategies imply the use of biocontrol agents,
the physiology, structure or function of another organism, displacing and eliminating phytopathogens. Among these agents,
facilitating the infection and/or triggering defense responses fungi classified in the Trichoderma genus are predominant. The
(Kamoun, 2006). This definition does not imply a positive or antagonistic capacity of Trichoderma has been widely studied,
negative impact on the outcome of the host–pathogen interaction and the mechanisms associated with it include competition
and therefore, can be applied to non-pathogenic interactions as for space and nutrients against its adversaries, antibiosis and
well (Thomma et al., 2011). mycoparasitism (Mukherjee et al., 2013).
In the plant–pathogen interaction, the participation of Some Trichoderma species can effectively colonize plant roots
elicitors has also been reported, and those are described as and shoots and establish a molecular dialogue, having a positive
a diverse group of molecules that induce plant defense in a effect in plants (Macías-Rodríguez et al., 2018; Manganiello et al.,
weak and non-specific fashion and independent of races or 2018). Mostafa and Gayed (1952) made the first observations in
cultivars (Alba et al., 2011). Additionally, it has been proposed this regard, reporting that Trichoderma improves fresh and dry
that the participation of highly conserved pathogen-derived weight in cotton plants. More than 20 years later, Catska et al.
molecules, with essential functions in the pathogens, for example (1975) reported that exudates from lettuce have a beneficial effect
chitin and flagellin, are needed for the establishment of the in conidia germination of Trichoderma viride, indicating that the
interaction with the host. Overall, these molecules are termed fungus and plants obtain mutual benefits.
Pathogen-Associated Molecular Patterns (PAMPs) and, since Moreover, an increasing amount of reports demonstrate
they have been described in non-pathogenic microorganisms, the that Trichoderma is an important plant endophyte that can
more general concept of Microorganism-Associated Molecular interact with plants such as maize, cucumber, cotton, tomato,
Patterns (MAMPs) is also used (Jones and Dangl, 2006). Because and Arabidopsis thaliana (Contreras-Cornejo et al., 2009;
of the wide distribution showed by elicitors, as well as their Vishnevetsky et al., 2010; Lopes et al., 2012; Mastouri et al.,
functional features, it was recently proposed to refer to them 2012; Reithner et al., 2014; Zhang et al., 2014; Lamdan et al.,
as PAMPs/MAMPs. In some cases, the distinction between 2015). Trichoderma penetrates the first or second layers of cells
PAMPs/MAMPs and effectors is not sufficiently defined, which of the epidermis in the root tissue or even colonizes intracellular
is mainly related to the fact that PAMPs/MAMPs are highly spaces and grows between the plasma membrane and the plant
conserved among genera, while effectors tend to be related cell wall (Yedidia et al., 1999; Nogueira-Lopez et al., 2018).
to a single or few related species. However, new studies have Colonization by Trichoderma promotes plant growth, biomass
uncovered that certain molecules classified as effectors are gaining, higher seed germination, increased plant height, root
also widely distributed among several species (Thomma et al., development, shoot dry mass and leaf number, increased crop
2011; Pazzagli et al., 2014). The debate about the functional yield and improved plant vigor (Harman et al., 2004; Salas-
classification of the molecules released by microorganisms Marina et al., 2015; Chagas et al., 2017). One of the most
remains open, and new evidence is necessary to clearly classify evident morphologic changes in plants triggered by Trichoderma
them and assign distinctive features for them. In order to is the increase of lateral roots, thus modifying root architecture.
avoid conceptual confusion, in this review, we will refer In this process, previous observations have demonstrated the
to effectors as those non-structural molecules derived from participation of auxins (Contreras-Cornejo et al., 2009) as well
microorganisms that have a function modulating the plant as a cross-talk between ET and auxins through the signaling
defense pathways and/or participating in the establishment of pathways mediated by MAP-kinases (Contreras-Cornejo et al.,
associations with plants. 2015). Also, the presence of Trichoderma not only modulates the
Plant defense response is based on the perception of levels of the hormones produced by the plant but Trichoderma
PAMPs/MAMPs inducing primary PAMP- or MAMP-immunity itself can contribute with its own hormones or could provide
(PTI/MTI), to counteract invading microorganisms (Jones and intermediates for the synthesis of some phytohormones, as a part
Dangl, 2006). The ‘effector-triggered immunity’ (ETI) is a of the benefits reported in the Trichoderma–plant interaction
second layer of defense, providing systemic resistance by sensing (Guzmán-Guzmán et al., 2019).
effectors from microorganisms to activate the induced systemic Recent research has confirmed that these fungi activate plant
resistance (ISR), mediated by jasmonic acid (JA) and ethylene defense pathways. However, how Trichoderma modulates the

plant immune response to establish a beneficial interaction is one development and reproduction. Finally, when the infection by
of the main challenges to be addressed. In the establishment of nematodes has already been established, T-79 intensely activates
the beneficial association between Trichoderma and plants, the the SA pathway, increasing the defense against subsequent attacks
effectors may play key roles, as demonstrated in mycorrhizal by juvenile nematodes. These results show that the effects of T-
systems such as Laccaria bicolor and Glomus intraradices 79 over the plants are a dynamic phenomenon, which can be
(Kloppholz et al., 2011; Plett et al., 2011). adapted to signals from other organisms in the near environment
Here, we will focus on the filamentous fungi Trichoderma spp. (Martínez-Medina et al., 2016).
and the efforts of the scientific community has done to identify
their effector molecules, as well as their role in the establishment
of a beneficial relationship with plants that promote growth and PROTEINS AS EFFECTORS IN
immune response activation. Trichoderma–PLANT INTERACTIONS
Proteins were the first molecules proposed as effectors and
PLANT DEFENSE RESPONSE AND ITS have been widely studied in pathogenic systems. There is
ACTIVATION BY Trichoderma not much information about Trichoderma effector proteins,
less than 20 effectors have been experimentally analyzed
One of the first observations related with the Trichoderma- during the interaction with plant systems (Table 1), among
induced ISR in plants was the induction of the hypersensitive them the following:
response (HR) and synthesis of phytoalexins in grapevine cell
cultures after the application of a cellulase from T. viride Cerato-Platanins
(Calderón et al., 1994). Trichoderma harzianum also increases These are non-catalytic secreted proteins, which contribute
the resistance of Phaseolus vulgaris against Botrytis cinerea to virulence in pathogens, acting as expansin-like
and Colletotrichum lindemuthianum (Bigirimana et al., 1997). proteins weakening cellulose aggregates from the cell wall
Arabidopsis mutants, impaired in JA biosynthesis, showed (Baccelli et al., 2013). The Small Proteins (Sm) Sm1/2/3 from
a similar level of root colonization to wild-type plants Trichoderma virens and their orthologs in Trichoderma
(Martínez-Medina et al., 2017). The opposite effect was observed atroviride Eliciting plant-response (Epl) Epl1/2/3 are produced
when impaired plants in the SA synthesis were analyzed. in the association with plants, playing different roles. Transcripts
These plants were unable to restrict the colonization by the and proteins corresponding to Sm1/Epl1 are detected as the most
fungus, indicating that SA-mediated response is implicated abundant in cultures supplemented with glucose or during the
in the regulation of the Trichoderma–plant colonization, thus interaction with tomato or maize plants (Djonovic et al., 2006;
preventing vascular system invasion (Alonso-Ramírez et al., Seidl et al., 2006; Gaderer et al., 2015). In maize, only the
2014). These two results suggested that ISR does not play a monomeric form of Sm1 or Epl1 proteins can induce the plant
relevant role during Trichoderma plant colonization, while SAR defense response and the dimeric form blocks the activation of
pathway modulates the root colonization extend. ISR. When T. virens and T. atroviride strains were cultured in
Moreover, other studies indicate that ISR induced by the presence of maize seedlings, Sm1 and Epl1 were produced
Trichoderma asperellum in cucumber was associated with as a glycosylated monomer and as a non-glycosylated dimer,
an increase in chitinase and peroxidase activity, as well as respectively. These results suggest that the signals released by the
the modulation of genes that are implicated in the JA/ET plant influence the state of glycosylation and multimerization
signaling pathways (Yedidia et al., 2000; Yedidia et al., 2003; of Sm1/Epl1 proteins that may control the Trichoderma–plant
Shoresh et al., 2005). molecular dialogue (Vargas et al., 2008). However, Sm2/Epl2
Trichoderma can also induce SAR defense even when ISR proteins are quantitatively fewer present that Sm1/Epl1 during
defense is activated and they can improve the plant resistance the interaction with maize, there is evidence showing that Sm2
against phytopathogens, such as Sclerotinia sclerotiorum, where and Epl2 are more relevant in the activation of defense and root
the effect of Trichoderma strains correlates with the production colonization in maize. The mechanism employed by Sm2/Epl2
of cell-wall degrading enzymes by the plant (Contreras-Cornejo to induce plant defense is unknown, but a strong reduction
et al., 2011; Salas-Marina et al., 2011; Lopes et al., 2012). In of the protection level of maize seedlings against Cochliobolus
pepper, Trichoderma stilbohypoxyli, Trichoderma Caribbaeum, heterostrophus was observed when plants were treated with the
and Trichoderma theobromicola altered the expression of the sm2/epl2 knockout strains in contrast with sm1/epl1 knockout
genes involved in the hypersensitive response and sesquiterpene strains (Crutcher et al., 2015; Gaderer et al., 2015).
phytoalexins biosynthesis (Bae et al., 2010). In a tripartite system,
involving pathogenic nematodes, T. harzianum T-79 and tomato Hydrophobins
plants, the presence of T-79 differentially primes the responses These are small surface-active proteins, which are only found
related to SA and JA in the plant. T-79 initially primes the in fungi. The genomes from T. virens and T. atroviride contain
SA pathway leading to a faster defense response, protecting the 17 sequences encoding for hydrophobins (Kubicek et al., 2011),
plant from the invasion. Later, the nematode suppresses the JA- and the upregulation of some of them has been reported
mediated defense pathway, but T-79 initiates its priming activity during Trichoderma–plant interactions. The expression of the
on this pathway, antagonizing the pathogen and reducing its hydrophobin-encoding gene HFB2-6 was down-regulated in the

TABLE 1 | Protein effectors from Trichoderma functionally validated during the interaction with plants.
Family Protein Trichoderma Function in interaction with plants References

strain
Cerato-platanins Sm1 (small protein 1) T. virens Induction of defense-related genes, production Djonovic et al., 2006,
of ROS and phenolic compounds. Djonovic et al., 2007;
Salas-Marina et al., 2015
Sm2 (small protein 2) T. virens Involved in root colonization and plant Crutcher et al., 2015
protection.
Epl1 (eliciting plant T. atroviride Induction of defense-related genes. Salas-Marina et al., 2015
response-like)
T. harzianum Induction of defense-related genes. Gomes et al., 2015
T. formosa Triggered of plant immune system. Cheng et al., 2018
T. asperellum Induction of defense-related genes. Yu et al., 2018
Swollenin (expansin-like protein) T. asperellum Involved in root colonization and induction of Brotman et al., 2008
plant defense.
Glycoside-hydrolases Thph1 and Thph2 (cellulase-like T. harzianum Induction of defense-related genes. Saravanakumar et al., 2016
protein)
Cellulases T. longibrachiatum Activation of plant defense pathways. Martínez et al., 2001
ThPG1 T. harzianum Involved on colonization of plant roots. Morán-Diez et al., 2009
Eix (xylanase) T. viride Triggers ET biosynthesis and hypersensitive Rotblat et al., 2002
response.
Hydrophobins HYTLO1 T. longibrachiatum Activate defense-related responses and growth Ruocco et al., 2015;
promotion. Moscatiello et al., 2018
TVHYDII1 T. virens Involved in colonization of plant roots. Guzmán-Guzmán et al., 2017
HBF2-6 T. asperellum Involved in root colonization and induction of JA Huang et al., 2015
and SA pathways.
TasHyd1 T. asperellum Involved in root colonization. Viterbo and Chet, 2010
The effectors are divided by families, we indicate the strain from Trichoderma that produce the protein effector and their function in plants.
presence of 1% poplar leaves powder, whilst the gene upregulated Rotblat et al., 2002). The cellulases, Thph1 and Thph2 from
under 1% poplar root powder, suggesting that HFB2-6 has T. harzianum, were applied on maize leaves and this treatment
a function in root colonization. Moreover, the recombinant led to the transient elevation of free cytosolic calcium and the
hydrophobin purified from E. coli activated the JA and SA production of reactive oxygen species (ROS). The 1Thph1- or
signal transduction pathways when used on poplar seedling. 1Thph2 null mutants were not able to upregulate the expression
Also, the upregulation of two genes related to auxin signaling of genes related to the jasmonate/ET signaling pathway in
was observed. Therefore, this protein seems to be involved in maize. By using the yeast two-hybrid system, Thph1 and Thph2
the promotion of growth and defense of poplar plants (Huang can bind to the autophagocytosis associated protein (ZmATG3)
et al., 2015). TVHYDII1, from T. virens, participates in the and germin-like protein (ZmGL) of the plant, respectively. The
colonization of tomato roots; this was demonstrated by using identification of this molecular interaction opens the possibility
null and overexpressing tvhydii1 strains (Guzmán-Guzmán et al., to analyze the cellular localization of these targets as well as their
2017). Likewise, the TasHyd1 from T. asperellum participates participation in the ISR (Saravanakumar et al., 2016, 2018).
in the colonization of cucumber plants (Viterbo and Chet,
2010). The purified hydrophobin HYTLO1 from Trichoderma CFEM and Small Secreted Cysteine-Rich
longibrachiatum activates the defense response and promotes Proteins (SSCPs)
plant growth. Moreover, knockout strains significantly decreased In Trichoderma spp., one of the most abundant groups of
their antagonistic activity and their capability to promote plant secreted proteins corresponds to small proteins containing four
growth (Ruocco et al., 2015). Therefore, HYTLO1 has a dual role or more cysteine residues. The SSCPs could be grouped into
in the process of interaction with plants. protein families with functions such as hydrophobins, some
glycosyl hydrolases, cerato-platanins, CFEM proteins (Common
Glycoside-Hydrolases in several Fungal Extracellular Membrane) as well as proteins
This is a wider group of proteins with enzymatic activity that are with unknown function (Druzhinina et al., 2012).
secreted by Trichoderma; some of them have been characterized Lamdan et al. (2015) reported a secretome analysis from
and implicated in the Trichoderma–plant interaction. The the interaction between T. virens and maize, detecting 13
xylanase Eix (ethylene induced xylanase) from T. viride triggers SSCPs negatively regulated by the presence of the roots. Plant
ET biosynthesis and the hypersensitive response in tobacco inoculation with independent knockouts strains, for four of these
plants, highlighting that the elicitation of ET biosynthesis is genes encoding the SSCPs (ID 92810, ID 71692, ID 111486, and
not related with Eix enzymatic activity (Sharon et al., 1993; ID 77560), showed an improvement in ISR activity compared

with the wild-type strain, without affecting root colonization. 2017). Additionally, the Tal6 protein from T. atroviride, was
SSCPs could act as negative effectors reducing the defense levels reported as an inhibitor of conidia germination (Seidl et al.,
in the plant and may be important for the fine-tuning of ISR by 2013); however, their direct participation with plants has not
Trichoderma. Bioinformatic predictions indicated the abundant been determined.
presence of SSCPs in T. atroviride and T. virens genomes, The differences in the experimental design in each case,
some of them containing CFEM domains, which are present where Trichoderma–Plant transcriptome/secretome are analyzed,
in cell surface proteins with important roles in the interaction makes it difficult to compare among all data sets to determine
with other organisms (Pérez et al., 2011; Druzhinina et al., the functional relevance of these genes. In the case of T. virens,
2012). Possibly, but not in all cases, CFEM proteins participate two secretomes obtained from hydroponic cultures, were
as negative regulators of plant defense. In the bioinformatic analyzed looking for proteins differentially expressed during their
analysis reported by Guzmán-Guzmán et al. (2017), there are interaction with maize seedlings. One of them analyzed the
32 sequences grouped as CFEM; among them the tacfem1 gene, soluble proteins, while the other focused only on the proteins
which was upregulated when the fungus was co-cultivated with found in the plant apoplast. The main differences between both
A. thaliana, suggesting a possible role during the establishment studies are related to the culture medium used and the time length
of the interaction. Also, in T. virens, the SSCP gene ID 19757 was of interaction. Lamdan et al. (2015) obtained the secretome
upregulated in the interaction with both maize and tomato, while from hydroponic cultures in sucrose-supplemented MS media
the ID 17705 gene was upregulated only by the presence of maize after 96 h of interaction, a total of 280 soluble proteins were
plants, rendering it a promising candidate for further analysis detected, of which 86% (241 proteins) contained a predicted
during the T. virens-maize interaction (Morán-Diez et al., 2015). signal peptide, identifying members of glycoside hydrolases
(GH), LysM proteins, CFEM, lipases, and SSCPs, including Sm1
Hunting for New Trichoderma Protein as the most abundant protein. From all secreted proteins, 66
Effectors were identified as differentially expressed, 32 were increased,
One of the main strategies to identify effector proteins is to while the remaining 34 showed a decrease when maize seedlings
analyze their upregulation in the presence of plants (Djonovic were present. Nogueira-Lopez et al. (2018) reported 43 secreted
et al., 2006; Plett et al., 2011; Guzmán-Guzmán et al., proteins, obtained from apoplastic space of maize roots cultured
2017). Trichoderma transcriptome and secretome analyses under in Hoagland’s solution after 60 h of interaction with T. virens, and
different culture conditions led to describe that cellulases, using a filtered-pipeline, nine of them were classified as putative
small proteins, and cytochrome p450, among others, are highly effector proteins. Both secretomes share 13 putative candidates,
represented (Lamdan et al., 2015; Morán-Diez et al., 2015; Rocha being the GH group; the most representative proteins with five
et al., 2016). Recently, a catalog of 233 putative effector proteins protein family members (Supplementary Table S1). The low
was reported from T. virens, T. atroviride, and Trichoderma reesei, number of common sequences could be due to the filtered-
identified and grouped in 18 families. The expression pattern pipeline used in each study or due to the differences in growth
of some of these genes was analyzed during the Trichoderma– conditions and sample collection times; without leaving aside the
Arabidopsis interaction, observing the upregulation of genes possibility that the roots could retain some proteins limiting their
grouped in LysM proteins, Serine-proteases, Thioredoxins, detection in the media (Lamdan et al., 2015).
Hydrophobins, CFEM, and Cerato-platanin families. Down- The comparison between each secretome with the proposed
regulation was also observed, as in the case of the Tvmp1 gene, T. virens effectors from the in silico analysis showed differences
encoding for a Metalloprotease (Guzmán-Guzmán et al., 2017), related to the number of effector candidates, which is expected
and for the Tvcyt2 gene, which encodes a p450-cytochrome given that the predicted secretome includes all sequences with the
(Ramírez-Valdespino et al., 2018). However, more than 200 potential of being effectors.
sequences from this in silico analysis were not studied further and Considering the full list of the apoplastic secretome (43
their possible function during Trichoderma–plants interaction proteins), the proteins found with differential expression in
remains unknown. the complete soluble secretome (66 proteins) and the effector
The LysM effectors play relevant roles in the establishment candidates from the in silico prediction (84 proteins), we only
of pathogenic interactions: they protect the fungal mycelium found the CFEM member (ID 92810) and the GH member (ID
by either covering the surface of the hypha, thereby interfering 42143) in the three research works, while 22 common sequences
with the enzymatic activity of the plant delivered chitinases were found between the soluble secretome (Lamdan et al., 2015)
or hijacking fungal cell wall derived chitin fragments, thereby with the predicted effectors (Guzmán-Guzmán et al., 2017).
avoiding the stimulation of the immune response (de Jonge Whereas, five sequences from the in silico analysis are present
et al., 2010; Kombrink et al., 2017). LysM encoding genes among the apoplastic secretome proteins, but they were not
are present in Trichoderma genomes, but they are not considered as effectors.
characterized as well (Mendoza-Mendoza et al., 2018). In The differences observed among the experimental strategies to
the catalog of putative effector proteins, there are 15 LysM identify new protein effectors in the association of Trichoderma
encoding genes, six belonging to T. atroviride and nine to with plants suggests that there is still no consensus to consider
T. virens. Additionally, the tvlysm1 gene was upregulated in co- products with the potential to participate as effectors, which
culture of T. virens with Arabidopsis, suggesting a role during represents a relevant topic to analyze further. The in silico analysis
Trichoderma interaction with the plant (Guzmán-Guzmán et al., can be less precise when identifying effector molecules, but

they provide a wide range of candidates to determine biological formation has been elucidated by metabolization of [U-14C]
functions and the best way to know the function of a putative and of [1-14C] linoleic acid in T. harzianum (Serrano-Carreon
effector is to perform a wide and specialized characterization. et al., 1993). In plants, 6-PP interferes with the signaling pathway
Understanding and identifying the effector proteins will provide involving auxins and ET, promotes plant growth, and regulates
tools to deepen our understanding on how plant-beneficial fungi root architecture by inhibiting the growth of the primary root
interaction is established and which could be the differences and inducing the formation of lateral shoots, by modulating
between a beneficial and a pathogenic system. the expression of genes encoding for auxin transporters. The
modification related to the lateral shoots is mediated by the
TIR1, AFB2, and AFB3 receptors and the ARF7 and ARF19
SECONDARY METABOLITES AS transcription factors, while the sensitization in the main root
EFFECTORS IN Trichoderma–PLANT is mediated by EIN2 (Garnica-Vergara et al., 2016). In field,
INTERACTIONS the application of 6PP (1 µM) or a spore suspension of
T. harzianum T22 (108 spore/liter) in Vitis vinifera, increased
One of the main characteristics of fungi is the production of a polyphenol content, antioxidant activity and weight in fruits
huge diversity of secondary metabolites (SMs); compounds with (Pascale et al., 2017). Cremenolide is a 10-member lactone
potential application in food, pharmaceutical and agricultural isolated from Trichoderma cremeum, that improved the root
industries (Brakhage, 2013). It is generally assumed that SMs length and fresh weight in tomato seedlings, but changes in plant
are not essential for growth and development in fungi but play height were not observed (Vinale et al., 2016).
important functions in the sensing, signaling and counteracting
processes for the organisms present in their environment Peptaibols
(Macheleidt et al., 2016). SMs comprise compounds of low These are small linear peptides of non-ribosomal synthesis, which
molecular weight, diffusible in the culture medium or volatile, usually have a high content of 2-amino-isobutyric acid (Aib)
which are synthesized through a great variety of pathways bound to unconventional amino acids, such as ethyl-valine,
(Brakhage, 2013). The synthesis of SMs is usually different isovaline, and hydroxyproline. There are at least 190 compounds
between strains, and is influenced by growth conditions (Yu of this type synthesized by Trichoderma species1 .
and Keller, 2005). At the molecular level, this environmental In T. virens, 18-mer peptaibols are produced through the
influence is related to the availability of regulatory elements. activity of the Non-Ribosomal Peptide Synthase (NRPS) encoded
In T. reesei, the SOR cluster contains two genes encoding for by the gene Tex1. This kind of peptaibols activates the plant
transcription factors involved in biosynthesis of sorbecillinoids, defense in Cucumis sativus against Pseudomonas syringae.
a group of yellow pigments with antimicrobial activities. YPR2, Cucumber plants growing in contact with T. virens increase
one of those transcription factors, carries out its major function the expression of three genes involved in the synthesis of
in constant darkness and in the presence of cellulose as a carbon phytoalexins, hpl, pal1, and prx, which encode for a hydroxy
source. The function of YPR is positively related to the levels of peroxide lyase, phenylalanine ammonia lyase, and peroxidase,
alamethicin and to the production of orsellinic acid in darkness respectively. The tex1 null mutants lose their ability to produce
(Hitzenhammer et al., 2019). In T. atroviride and T. virens, it has 18-mer peptaibols, leading to a lower expression of hpl, pal1,
been shown that heterotrimeric G proteins, mitogen-activated and prx genes in plants. The use of two synthetic peptaibols
protein kinases (MAPK) and transcription factors are involved TvBI and TvBII on cucumber seedlings activated systemic
in the signaling pathway leading to SMs synthesis, which also protection against bacteria and induced the expression of hpl,
respond to environmental conditions as a type of nutrients, pal1, and prx (Viterbo et al., 2007). Null mutants in ppt1
pH, light or temperature (Reithner et al., 2005; Mukherjee gene, which codes for a 4-phosphopantetheinyl transferase in
and Kenerley, 2010). Antibiotic activity has been reported for T. virens, are affected in the synthesis of 11, 14, and 18-
SMs produced by Trichoderma species against various yeast, mer peptaibols, although their capability to colonize roots is
filamentous fungi and bacteria, causing growth inhibition or cell not affected. Furthermore, antibiosis on phytopathogens, as
death. These SMs, acting synergistically with hydrolytic enzymes, well as the ability to induce the synthesis of SA and of
are more likely to be implicated in the effectiveness of the strain camalexin in Arabidopsis plants, is compromised in these strains
producing them as a biological control agent (Reino et al., 2008). (Velázquez-Robledo et al., 2011).
Although the metabolites produced by plants could also affect Alamethicin is one of the most studied peptaibols due
the association with microorganisms, either by favoring it or by to its ability to induce defense responses in plants such as
restricting it, in this section we will focus on those SMs produced callose deposition, expression of genes related to plant defense,
by Trichoderma species that have shown impact in their capacity production of SMs, and accumulation of phenolic compounds,
as plant symbionts. that together can improve the vigor of plants and their response
to stressing conditions (Rippa et al., 2010). In A. thaliana,
Lactones the presence of alamethicin interferes with the synthesis of
These are generally very pleasant, potent, flavor materials, which methy farnesoate (MeFA), an SM related to herbivory, by
are widely distributed in nature (Kapfer et al., 1989). The best- altering the presence of the miRNA163, which targets genes
known SM for Trichoderma species is 6-pentyl-2H-pyran-2-
one (6-PP), derived from linoleic acid and the pathway of its 1
http://peptaibol.cryst.bbk.ac.uk/home.shtml

encoding methyltransferases relevant in the synthetic pathway Trichothecenes

of the MeFA (Ng et al., 2011). It is proposed that alamethicin Trichoderma brevicompactum produces trichodermin through a
increases ion permeability in the cell membrane (Duclohier pathway involving the activity of p450 enzyme, encoded by Tri5
and Wróblewski, 2001). Trichokonin VI (TK VI) is produced gene. The overexpressing strains of this gene had a negative
by T. longibrachiatum SMF2, and it has been shown that this effect in tomato plants, decreasing the root length and plant
peptaibol interferes with the GORK channel, a rectifying K+ size (Malmierca et al., 2015). Harzianum A (HA), isolated from
channel gated outwardly, which alters the root structure by T. arundinaceum, did not show any effect over growth of tomato
inhibiting cell division and elongation in the main root. TK VI seedlings. However, mutant strains that do not produce HA
increases the auxin content and interrupts its gradient at the tips were impaired to upregulate the expression of genes involved
of the roots, interfering with the local synthesis and its polar in plant defense at the same level. HA could be sensitizing
transport (Shi et al., 2016). the plant cell to induce those genes faster and at higher levels
(Malmierca et al., 2012).
Polyketides
These are one of the most abundant groups of SMs in nature,
which includes macrolides, polyenes, and polyphenols. They have
Volatile Organic Compounds (VOCs)
been studied in detail because the group includes compounds The VOCs group includes several small compounds with
with an impact on human health such as sterigmatocystin, different chemical natures, playing relevant roles as essential
aflatoxin B1 and lovastatin. They are produced by polyketide signals in interactions among plant roots, microbes, and insects
synthases (PKSs), multi-domain proteins similar to fatty acid (Schenkel et al., 2015). The effect by the VOCs produced by
synthases, which condense acetyl coenzyme A or malonyl 25 different Trichoderma strains on the plants were analyzed
coenzyme A units, to form carbon chains of variable length using A. thaliana as a host, in two independent research
(Chiang et al., 2010). In Trichoderma arundinaceum, the works. The general results showed that one of the strains
production of 4 aspinolides has been reported, in particular, produced VOCs with a negative impact on plant growth,
aspinolide C participates in the induction of genes PR1b1, 10 of the strains did not have any obvious effect on the
PR-P2 involved in the signaling pathway mediated by SA. plants, while fourteen of them had a positive effect on total
During the interaction of T. virens with maize plants, the biomass and on chlorophyll content. The analysis of the
expression of the defense-related genes pal1 and aos (allene VOCs produced by each strain determined the presence of
oxide synthase) is increased. This upregulation is related great diversity of compounds, suggesting the participation of
to SMs produced by T. virens through the activity of the several mechanisms to generate the final effect on plants
PKS/NPRS encoded by the Tex 13 gene. Strains affected in (Lee et al., 2016; Nieto-Jacobo et al., 2017). This blend of
Tex13 retained their ability to increase the expression of the compounds present in VOCs makes it difficult to determine
gene aos in plant, but they could not upregulate the pal1 gene which of the metabolites is responsible for the effects observed
(Mukherjee et al., 2012). on the plants. Some strategies that could help to define
their biological role are based on genetic manipulation in
Terpenes order to generate strains affected in key elements of the
These are a highly diverse family of SMs at the structural and VOCs biosynthesis. Trichodiene (TD) is a VOC used as
stereochemical level. These molecules are derived from long a substrate by the sesquiterpene synthase Tri5 to produce
polyisoprenoid diphosphates that can be cyclized to generate the compound Harzianum A (HA) in T. arundinaceum. The
single or multiple ring products. The cyclization reactions are heterologous expression of the gene Tri5 in T. harzianum
carried out by high-affinity terpene cyclase enzymes, which led to the production of TD. VOCs released by this Tri5-
generate a single product or by promiscuous enzymes that transformant and TD itself induced the expression of tomato
can generate up to 52 different products (Christianson, 2008). defense genes related to SA (Malmierca et al., 2015). In
Cytochrome p450 enzymes are involved in the reactions T. atroviride, the mutation of genes encoding membrane-
of synthesis and/or modification of terpenes. Recently 477 bound NADPH oxidases (Nox), leads to the alteration of VOCs
cytochrome P450s have been identified from seven Trichoderma profiles. Loss of function of Nox1 or the regulator NoxR,
species (Chadha et al., 2018). Cytochrome p450 activity is in the presence of a functional Nox2 enzyme leads to the
needed for the synthesis of SMs, which are related to the production of VOCs with inhibitory effects on plant growth
mycoparasitic capacity and/or its association with plants. The (Cruz-Magalhães et al., 2019).
enzyme encoded by the G3 gene in Trichoderma hamatum
is activated in response to Sclerotinia and Sclerotium species Phytohormones
(Carpenter et al., 2008). Through the generation of mutant and Phytohormones are important growth regulators with relevant
overexpressing strains of the Tvcyt2 gene of T. virens, five terpene- roles on metabolism and plant defense responses. Several root-
like compounds were identified as involved in the antagonistic associated microbes are able to produce phytohormones that have
activity against Rhizoctonia solani, in the activation of genes an effect in plants (Egamberdieva et al., 2017). T. virens produces
related to the JA pathway in Arabidopsis plants as well as in Indole-3-acetic acid (IAA) and indole-3-acetaldehyde (IAAId),
the promotion of growth in Arabidopsis and tomato seedlings which promotes plant growth and development in A. thaliana
(Ramírez-Valdespino et al., 2018). (Contreras-Cornejo et al., 2009).

Cytokinins (CKs) are essential molecules that regulate plant maize, the use of T. harzianum T22, one of the most widely
growth and development (Osugi and Sakakibara, 2015). ET is used commercial strains, induced strong positive growth over
a volatile hormone that regulates a range of processes, from eight maize hybrids tested, it had little effect on growth over
seed germination, organ senescence, among others (Bleecker eight other hybrids and it even negatively affected growth of
and Kende, 2000). CKs promote hyphal branching and help two other maize hybrids (Harman, 2006). While in tomato,
in oxidative stress tolerance in Magnaporthe oryzae (Chanclud independent symbiotic interactions between T. harzianum T22
et al., 2016), whilst in mycorrhizal fungi, ET affects spore or T. atroviride P1 with four Solanum lycopersicum lines
germination and growth (Barker and Tagu, 2000). There are or the wild Solanum habrochaites accession demonstrated
no reports in Trichoderma about CKs or ET production, that genetic variability is a determinant in the response
though in the genome of T. atroviride, the genes necessary shown by plants related to growth, weight, resistance against
to synthesize both compounds are present, suggesting that it B. cinerea and the expression of genes involved in plant defense
could produce these phytohormones, with a potential impact (Tucci et al., 2011).
in the association with plants (Guzmán-Guzmán et al., 2019). We propose that many SMs can be classified as effectors and
Abscisic acid (ABA) is involved in seed dormancy and the different Trichoderma–plant systems developed by different
development, abiotic stress response, among other roles in work groups make evident the utility of using them as a
plants, and there is evidence of its production by several fungi biological model. Metabolomic analysis, involving the study of
on which ABA was proposed as a factor promoting plant the concentrations, structures and interactions of thousands
colonization (Charpenter et al., 2014; Chanclud and Morel, of SMs represents a useful tool to identify molecules with
2016). There were six genes related to the ABA biosynthesis potential biotechnological application in the improvement of
pathway identified in T. atroviride. However, no homolog plant yield and vigor.
to bcaba3/ataba3, a gene encoding a key enzyme in last
steps of the biosynthesis of ABA was found, suggesting that
T. virens is unlikely to produce this phytohormone and that Trichoderma’s SMALL RNAs AS
it could only provide an ABA intermediary (Guzmán-Guzmán PUTATIVE EFFECTORS
et al., 2019). Additionally, it was proposed that T. virens
and T. atroviride modulate ABA-regulated responses, such Thus far, plant analysis has focused on the identification of
as stomatal aperture and leaf transpiration in A. thaliana proteins involved in the plant immune response. However,
(Contreras-Cornejo et al., 2015). several lines of evidence have shown that plants also use
non-coding RNAs against pathogens (Pumplin and Voinnet,
Factors That Influence the Effect of SMs 2013) and symbionts (Pieterse et al., 2014). Small RNAs
on Plants (sRNAs) play important roles in plant immune responses
Three relevant factors related to the positive effect generated against virus, bacteria, fungi, and oomycetes (Pumplin and
on the plants by SMs are, the dose used of each SM, the Voinnet, 2013). sRNAs are 20–30 nucleotide long non-coding,
physiological state, as well as the genetic background of the sequence specific regulatory RNA molecules that mediate gene
plants tested (Vinale et al., 2009; Li et al., 2019). The effect silencing to regulate physiological and developmental processes
of alamethicin over plants has been tested at high doses such (Chang et al., 2012; Pumplin and Voinnet, 2013). In plants,
as 10 and 50 mM. When these are applied to Arabidopsis sRNAs are processed from double-stranded or single-stranded
seedlings, they generate plant death and this toxicity is related RNA with hairpin structures by Dicer-like (DCL) proteins,
to cleavage of ribosomal RNA and cellular lysis. The use of which release RNA duplexes. After processing, sRNAs are
alamethicin at lower doses (5 µM) suggest that a threshold in loaded into RNA-induced silencing complexes (RISC), which
the concentration of this SM is required to trigger only plant- contains one member of the ARGONAUTE (AGO) protein
cell permeabilization and induce programed cell death as a family, leading to transcriptional gene silencing by guiding
hypersensitive response, showing similarities with the response heterochromatin formation, inhibiting mRNA translation or
elicited by avirulent pathogens or by compounds that mimic inducing mRNA degradation. Several members of the sRNA
a pathogen attack (Rippa et al., 2007; Rippa et al., 2010). biogenesis machinery are involved in plant immunity, including
Koninginins A, B, C, E, and G tested at 10−3 M, inhibited DCL, AGO, DCL associated proteins and RNA dependent RNA
growth of etiolated wheat coleoptiles at different rates, varying polymerases (RDRs). Mutants in such genes show defects in
between 54 and 65% and up to 100% (Reino et al., 2008). sRNAs accumulation and are impaired in pathogen response
Treatments of 6-PP over A. thaliana seedlings in doses from (Seo et al., 2013).
50 to 175 µM increased shoot, root and total plant biomass During the last decade, cross-kingdom RNA interference
while at 200 µM, no increase in biomass was observed. 6- (RNAi) between host and phytopathogens has demonstrated
PP also raised both lateral root number and density in a its role in the successful colonization of plant tissues by the
dose- dependent manner, showing an inhibition of primary phytopathogens or in their avoidance by the plant. For instance,
root growth from 125 µM onwards, without cell damage host-induced gene silencing (HIGS), a technology developed
(Garnica-Vergara et al., 2016). to protect crops from fungal infections by expressing dsRNA
The plant genetic background is a determinant in the in planta to silence virulence genes, enhances plant resistance
response generated by specific strains of Trichoderma. In to Fusarium verticillioides or Blumeria spp. upon infection of

the host plant (Nowara et al., 2010; Tinoco et al., 2010). HIGS plant. Interestingly, target genes encode lytic enzymes, MAPKs
technology is also effective against Puccinia spp. (Yin et al., 2011, putatively involved in plant immunity, proteins with a domain
2014), Fusarium spp. (Koch et al., 2013; Hu et al., 2015) and of unknown function, disease resistance protein, NBS-LRR
S. sclerotiorum (Andrade et al., 2016). class family proteins, and S-Adenosyl-L-Methionine-dependent
B. cinerea, produces complementary sRNAs against plant methyltransferases superfamily proteins, among others. This
immunity related genes in Arabidopsis and Lycopersicum indicates that T. atroviride could be using sRNAs as effector
esculentum (Weiberg et al., 2013). Upon infection of Arabidopsis molecules, similarly to B. cinerea and V. dahliae, to establish
by B. cinerea, the fungal sRNAs associate with Arabidopsis AGO1 a symbiotic relationship with Arabidopsis through interfering
protein, interfering with plant target mRNAs, for example, those mRNAs involved in plant immunity, chromatin modifications
encoding MAPKs. These findings indicate that the fungus hijacks and cell wall degrading enzymes, among others that remain to
the host RNAi machinery to silence the host own genes (Weiberg be determined. However, more research is needed to unravel
et al., 2013; Wang M. et al., 2017). Moreover, Arabidopsis ago1- the molecular mechanisms mediated by the fungal sRNAs that
27 mutants are more resistant to B. cinerea infection, supporting allows us to better understand the mechanisms that lead to the
that the fungus uses the plant RNAi machinery to silence establishment of this beneficial association.
host genes. Transferred fungal sRNAs into the plant cell are
detected in B. cinerea dcl1 or dcl2 single mutants, but not
in a dcl1/dcl2 double mutant, leading to a diminished fungal CONCLUSION
virulence, indicating that the biogenesis of sRNAs is required
for pathogenesis (Weiberg et al., 2013). Transgenic plants The consequence in the field of the presence of Trichoderma
expressing one of these sRNAs (Bc-siR37) silence Arabidopsis on plants can be indirect, for example by exerting antagonistic
genes encoding a pectin lyase, a WRKY transcription factor, and activity on potential phytopathogens, by attacking them, and
a receptor-like kinase (Wang M. et al., 2017). The causal agent
of wheat stripe rust disease, Puccinia striiformis, silences the
mRNA that encodes for the PR-2 protein, through Pst-milR1, a
miRNA-like sRNA (Wang B. et al., 2017). In Verticillium dahliae,
it was shown that AGO2 does not play a role in the infection of
Arabidopsis. This pathogen infected Arabidopsis ago2-1 normally,
whereas in ago1-27 mutant, the rate of infection was reduced
(Wang et al., 2016).
Successful establishment of the Trichoderma–plant interaction
during early stages of root colonization implies the activation
of cell detoxification and protection mechanisms in the fungi
(Ruocco et al., 2009; Estrada-Rivera et al., 2019). Therefore, these
fungi possess effective systems that efficiently scavenge harmful
compounds from the cell. This has been partially shown with
the suppression of phytoalexin and plant genes related to the
defense mechanisms in Lotus japonicus and Arabidopsis during
its interaction with Trichoderma koningii and T. atroviride.
Application of these fungi to plant roots induced a rapid
accumulation of host transcripts that encode key enzymes of
SAR and ISR and those involved in phytoalexin synthesis.
The expression of these genes is transient and decreased to
levels of the control plants. Trichoderma resembles mycorrhizal
fungi in the establishment of symbiotic associations rather than
fungal pathogens (Masunaka et al., 2011; Estrada-Rivera et al.,
2019). Production of sRNAs by filamentous fungi, including
Trichoderma species, has been documented. Although analysis
of mutants in the biogenesis components of sRNAs in fungi
have shown their role on their biology (Chang et al., 2012;
Carreras-Villaseñor et al., 2013), much is yet to be explored
regarding the roles of sRNAs in this kingdom. There is no
direct evidence for the role of beneficial microorganisms sRNAs FIGURE 1 | Effectors participate during Trichoderma–plant interaction.
on the suppression of plant immunity to establish a symbiotic Antagonist activity of Trichoderma against phytopathogenic fungi. The release
relationship. In our group, we sequenced sRNAs libraries during of molecules from Trichoderma with activity as effectors is highlighted. These
molecules will modulate the plant hormonal balance as well as its defense
Arabidopsis–T. atroviride interaction at different interaction
response, allowing colonization. The beneficial association will result in the
times. Mapping the sRNAs over the T. atroviride genome revealed improvement of plant growth and in the resistance against phytopathogens.
that 37 sRNAs of the fungus matched with genes of the host

by colonizing the rhizosphere, so they can avoid the contact but its relevance in fungus–fungus associations is still pending,
of the pathogen with plant tissue. Direct beneficial effects on highlighting the idea of a multidirectional molecular exchange in
plants by Trichoderma are related to root colonization, although the rhizosphere.
in many cases it has been shown that direct contact may not
be necessary. Effectors of Trichoderma may play a key role in
the success of colonization of the plant, first by establishing the AUTHOR CONTRIBUTIONS
initial contact and subsequently maintaining the fungus–plant
interaction (Figure 1). Many of the effectors that have been CR-V, SC-F, and VO-M contributed equally with ideas and
identified in Trichoderma, and in other fungal symbionts, have discussion material. VO-M coordinated the work. CR-V
reported activities described in their pathogenic counterparts. wrote the review.
Therefore, the success of the interaction must not only rely
on molecules playing these functions. The physiological state
of both participants, as well as their threshold of perception FUNDING
toward the molecular signals exchanged are also important
factors. This regulation does not depend solely on the genetic Research conducted by the groups, related to the topics of this
background of the fungus, the signals generated by the plant review was supported by CONACyT grants CB-286709 and FC-
are also important. The study of effectors in Trichoderma is a 2016-1538 conferred to VO-M and SC-F, respectively.
relatively recent topic; however, thanks to technological advances
to detect, identify and quantify molecules (proteins, secondary
metabolites, and RNAs), the scientific community already has ACKNOWLEDGMENTS
an extensive catalog of effector candidates. In most cases, it
is necessary to carry out biological validation and determine We would like to thank Bernardo Franco-Bárcenas Ph.D. for his
the spectrum of action of these effectors on different plants useful suggestions and corrections and Roberto Gámez-Ramírez
at the level of cultivars, species and even genera. Moreover, for his support to make the drawing in Figure 1.
the analysis of the interaction, considering longer times, may
indicate how Trichoderma can change the plant physiology,
during its complete life cycle. Due to the versatility shown by SUPPLEMENTARY MATERIAL
Trichoderma to associate with a wide variety of plants, it would
be possible to determine the relevance of those candidates in The Supplementary Material for this article can be found
different plant systems. In this review, we have focused mainly online at: https://www.frontiersin.org/articles/10.3389/fmicb.
on the participation of the effectors in the interaction with plants, 2019.01030/full#supplementary-material
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published: 15 May 2019

Trichoderma as a Model to Study

Plants are capable of perceiving microorganisms by coordinating processes to establish

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Family Protein Trichoderma Function in interaction with plants References

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encoding methyltransferases relevant in the synthetic pathway Trichothecenes

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