Engineering pathogen resistance in crop plants current trends and future pros...
Kumari2016
1. MINI-REVIEW
Multifaceted impact of trichothecene metabolites
on plant-microbe interactions and human health
Indu Kumari1
& Mushtaq Ahmed1
& Yusuf Akhter2
Received: 16 March 2016 /Revised: 4 April 2016 /Accepted: 29 April 2016
# Springer-Verlag Berlin Heidelberg 2016
Abstract Fungi present in rhizosphere produce trichothecene
metabolites which are small in size and amphipathic in nature
and some of them may cross cell membranes passively.
Hypocreaceae family of rhizosphere fungi produce trichothe-
cene molecules, however it is not a mandatory characteristic
of all genera. Some of these molecules are also reported as
growth adjuvant, while others are reported as deleterious for
the plant growth. In this review, we are exploring the roles of
these compounds during plant-microbe interactions. The
three-way interaction among the plants, symbiotic microbial
agents (fungi and bacteria), and the pathogenic microbes (bac-
teria, fungi) or multicellular pathogens like nematodes involv-
ing these compounds may only help us to understand better
the complex processes happening in the microcosm of rhizo-
sphere. These metabolites may further modulate the activity of
different proteins involved in the cell signalling events of
defence-related response in plants. That may induce the de-
fence system against pathogens and growth promoting gene
expression in plants, while in animal cells, these molecules
have reported biochemical and pharmacological effects such
as inducing oxidative stress, cell-cycle arrest and apoptosis,
and may be involved in maintenance of membrane integrity.
The biochemistry, chemical structures and specific functional
group-mediated activity of these compounds have not been
studied in details yet. Few of these molecules are also recently
reported as novel anti-cancer agent against human
chondrosarcoma cells.
Keywords Secondary metabolites . Plant growth promoting
fungi . Trichothecene . Bioherbicide . Anti-cancer agent .
Plant-microbe interaction
Introduction
Secondary metabolites (SMs) produced by the fungi residing
in the rhizosphere of plants play important roles in modulating
the microenvironment of the host cell for benevolence/malev-
olence, the virulence and the lifestyle of the microbial plant
pathogens as well as the plant growth promoting fungi
(PGPF); only some of the fungal SM biosynthetic gene clus-
ters have been characterized functionally (Malmierca et al.
2012; Pusztahelyi et al. 2015; Sharma and Kim 1991). Most
of the SMs are produced by the fungal group belong to the
order Hypocreales; the fungal genera producing the SMs in-
clude Fusarium, Myrothecium, Verticimonosporium,
Stachybotrys, Trichoderma, Trichothecium, Cephalosporium
and Cylindrocarpon (Ahmed and Upadhayay 2009; Ismaiel
and Papenbrock 2015). The fungal SMs namely trichothe-
cenes exhibit multiple impacts (advantageous and disadvanta-
geous) on the plants, microbes and animals (Fig. 1) (Table 1).
Some of these compounds produced by Fusarium spp. have
been reported to inhibit the plant seed germination and result
in callose deposition, hydrogen peroxide-induced pro-
grammed cell death, accumulation of salicylic acid and alter-
ation in the ascorbate metabolism in plants (Nishiuchi et al.
2006; Paciolla et al. 2004; Pusztahelyi et al. 2015). It was also
reported that simple trichothecenes may act as bio-control
* Yusuf Akhter
yusuf@daad-alumni.de; yusuf.akhter@gmail.com
1
School of Earth and Environmental Sciences, Central University of
Himachal Pradesh, ShahpurKangra District, Himachal
Pradesh 176206, India
2
School of Life Sciences, Central University of Himachal Pradesh,
ShahpurKangra District, Himachal Pradesh 176206, India
Appl Microbiol Biotechnol
DOI 10.1007/s00253-016-7599-0
2. Nematode
Trichothecne molecules
Nematicidal effect of mycotoxin
(trichothecene) and hydrolytic enzymes ?
Trichothecene molecules interact with
which receptors?
Action mechanism of trichothecene
molecules in inhibiting egg and cyst
development?
Pathogenic fungi
Alters expression of virulent genes e.g. atrB and pg1
Accumulation of antimicrobial proteins
Direct elicitation of defense genes
Oxidative stress induced defense genes
Potential anti-cancer
agents
Plant tissue
Fig. 1 Trichothecene molecules showed varied role in the field of
agriculture: Fungi present in rhizosphere of the plant produce these
compounds which fortify the plants against the pathogenic microbes
and pests (Pusztahelyi et al. 2015). These compounds were reported to
increase the expression of defence-related genes and causing the
strengthening of the cell wall. The expression of virulence genes of the
pathogenic fungi is altered by these compounds (Jain et al. 2013;
Malmierca et al. 2015). The egg hatching and early stages of development
of pathogenic nematodes were reported to be affected in the presence of
trichothecenes (Nitao et al. 2001)
Table 1 Trichothecene molecules have shown diverse effects on the plant cells and the animal cells. It was observed that these compounds may help to
improve the practices of sustainable agriculture. Some of these molecules were also reported to be beneficial in the field of medicine
SR. NO. Trichothecene compound Activity
1. Type A Neosolaniol Bioherbicide (Zonno and Vurro 1999)
Diacetoxyscirpenol Potential nematicide (Nitao et al. 2001)
T2-toxin Potential endocrine disrupting compound (Ndossi et al. 2012)
HT2-toxin Potential immunosuppressive agent (Masuda et al. 1982)
Trichodermin Bio-control activity (Shentu et al. (2014)
Hrazianum A Bio-control activity (Malmierca et al. 2012)
Monoacetoxyscirpenol Phytotoxic (Ismaiel and Papenbrock 2015)
2. Type B Nivalenol Potential nematicide (Nitao et al. 2001)
Deoxynivalinol Phytotoxic, affect gastrointestinal homeostasis, growth,
neuroendocrine function, and immunity of animals (Mishra et al. 2014)
Trichothecene Potent anti-tumour activity (Su et al. 2013)
Fusarenon X Potential immunosuppressive agent (Masuda et al. 1982)
3. Type C Crotocin Phytotoxic (Ismaiel and Papenbrock 2015)
4. Type D Satratoxins Induce apoptosis and genotoxic (Nusuetrong et al. 2012)
Verrucarin A Potential candidate for therapy of diabetes, obesity and
disorders related with dysfunction of ER stress (Bae et al. 2015)
Roridins Bioherbicide (Hoagland et al. 2012)
Appl Microbiol Biotechnol
3. agents, strengthen the defence system of the plants against the
pathogenic microbes including rhizoparasites like nematodes
(Fig. 1). Although knowledge about how trichothecenes inter-
act with the receptors and the proteins involved in the elicita-
tion of defence system of the plants at the molecular levels is
limited, these reported as potential candidates which may be
developed into bioherbicides and anti-cancer agents. It was
also reported that the toxicity of trichothecenes can be lowered
by acetylation/peracetylation of hydroxyl groups. The remov-
al of isovaleryl and acetyl groups from type A trichothecenes
resulted in decreased toxicity to yeast (Abbas et al. 2013;
Madhyastha et al. 1994). The chemical structure of these com-
pounds is known as sesquiterpenoids that share a common
core comprised of a rigid tetracyclic ring system, and the main
substitution sites are R1 to R5 (Table 2). Studies on
hydroxylation/acetylation showed that de-epoxide metabo-
lites of the type A trichothecenes T-2 toxin and
diacetoxyscirpenol (DAS) were served to be less toxic
(Swanson et al. 1987, 1988), while the genes involved in the
detoxification pathway are being investigated (Boutigny et al.
2008). Gardiner et al. (2010) reported that barley exhibits
multiple defence mechanisms against trichothecenes. The
analysis has shown increased gene expression of ABC trans-
porters, UDP-glycosyltransferases, cytochrome P450s, gluta-
thione-S-transferases and cysteine synthases. It was further
observed that it stemmed into depletion of glutathione which
have capacity to reduce the impact of trichothecene molecules
(Gardiner et al. 2010). This interplay of gene expression from
various pathways and organelles of the cells provide the pos-
sible candidates involved in the detoxification of the tricho-
thecenes; further studies to validate these genes and their cor-
relation with other metabolic pathways of the cells will be
helpful for the better understanding of their function and their
practical application in the field of agriculture and medicine. It
is reported that trichothecenes showed different hydrogen
bond behaviour in solid/solution state that lead to conforma-
tional differences in solution state where the epoxide is free to
form hydrogen bond (Chaudhary et al. 2011). The trichothe-
cene core of deoxynivalinol (DON) is constituted by flexible
groups (i.e. –OH and –H) with an exceptional C-8 ketal func-
tionality which may result in the significant rigidity of the
system. The structural analysis of DON has shown that the
intramolecular hydrogen bonding is present in DON and water
can bind within the tetrahydropyranyl pocket of the DON.
Regarding the potential of DON to form intramolecular hy-
drogen bonds was attributed to its existence in more than one
stable conformation (Nagy et al. 2005). Further studies are
needed to investigate the structural behaviour of all of the
trichothecenes, as some of them are beneficial and others are
harmful. It is evident that trichothecenes inhibit protein trans-
lation by interacting with peptidyl transferase centre (PTC) of
the ribosomal complex and, therefore, further studies about
the local environment of the binding pocket of PTC, where
the binding site for T2-toxin trichothecene molecule exists,
will be helpful in better understanding of its mechanism of
inhibition (de Loubresse et al. 2014). The expression of
fadAG42R
which encodes the subunit of a heterotrimeric G-
protein in Fusarium sporotrichioides increases trichothecene
mycotoxin production and alters its biosynthetic genes expres-
sion differentially (Tag et al. 2000; Patel et al. 2016). This
provides an initial step towards targeting G-protein signal
transduction pathways as a means to control/prevent the pro-
duction of a single mycotoxin. If we are able to understand the
steps involved in this pathway, there is possibility of con-
trolled synthesis of required trichothecene and its better bio-
technological application. Different fungi (for instance
Paecilomyces lilacinus, Verticillium chlamydosporium,
Cylindrocarpon destructans, Pochonia chlamydosporia,
Fusarium spp. and Penicillium spp.) may be found on the
cysts, eggs and the larvae of the nematodes which parasitize
the helminths (e.g. Heterodera, Globodera and Meloidogyne)
(Mazurkiewicz-Zapałowicz and Kołodziejczyk 2008; Nitao
et al. 2001). It has to be investigated whether these compounds
alter the expression of genes which encode for vitellogenin
and choriogenin (provide protection and nutrition to the de-
veloping embryo of the nematode), membrane proteins and
other important proteins. However, effective application of
biocontrol agents in the field requires a comprehensive under-
standing of the ecology and population genetics of the PGPF,
host, pathogenic microbes and the pathogenic nematodes,
commonly found in natural rhizospherical niche. Even though
there is antagonism between the fungi and the nematodes is
commonly observed event in the microcosm, but still the nem-
aticidal and nematotoxic properties of fungi derived SMs have
not been used in a wide application in biological plant protec-
tion. We have reviewed current state of knowledge available
on different types of trichothecene SMs involved in the
pathogen-symbiont-plant interface and their useful and dele-
terious effects on this interaction and its effect on animal cells.
Types of trichothecene molecules
The trichothecenes are divided into microtrichothecenes
(Types A, B and C) and macrotrichothecenes (Type D).
Type A trichothecenes tend to be far more toxic to animals
and humans than they are for the plants (Shank et al. 2011).
Microtrichothecenes
These are distinguished by modification at the C-8 position.
Type A trichothecenes are the simplest, being non-
substituted, hydroxylated at C-8 position e.g. neosolaniol,
DAS, T2-toxin, HT2-toxin, trichodermin, harzianum A
(HA), monoacetoxyscirpenol or MAS (Strub et al. 2010)
(Table 1). Type B trichothecenes contain a ketone group
Appl Microbiol Biotechnol
4. present at C-8 position e.g. nivalenol (NIV), DON, tricho-
thecene and fusarenon X (Alexander et al. 2011; Audenaert
et al. 2013; Kimura et al. 2007) (Table 1). Type C tricho-
thecenes (e.g. crotocin) are less common than the others
and are differentiated by the presence of a second epoxide
ring at C-7/8 position (Ismaiel and Papenbrock 2015)
(Table 1). The structural analysis of T2-toxin showed that
it is involved in water-bridging interaction with different
liquid media that lead to slow down the exchange of water
which may be a possible reason for its toxicity (Chaudhary
Table 2 Structure of trichothecene core of different trichothecene
molecules with its functional groups. Chemical structure of
trichothecene molecules shows a common trichothecene core i.e.
epoxide ring which provide stability to these molecules and different
side chains/functional groups which may contribute to their varying be-
haviour and biological activities inside/outside of the cells
Compound Core structure of different
classes of trichothecene
molecules
Name of
trichothecene
Side chain of the compound
R1 R2 R3 R4 R5
Type A Neosolaniol OH OAc OAc H OH
Diacetoxyscirpenol OH OAc OAc H H
T2-toxin OH OAc OAc H OCOCH2
CH(CH3)2
HT2-toxin OH OH OAc H OCOCH2
CH(CH3)2
Trichodermin OH OAc CH3 H H
Hrazianum A OH CH3 H H
Monoacetoxyscripenol OH OH OAc H H
Type B Nivalenol OH OH OH OH
Deoxynivalinol OH H OH OH
Trichothecin OH OCOCH=CHCH3 OH OH
Fusarenon X OH OAc OH OH
Type C Crotocin H OCOCH=CHCH3
Type D Roridin A
VercurrinA
Satratoxins
Appl Microbiol Biotechnol
5. et al. 2011). Trichodermin is reported to have an antifungal
activity against the pathogenic fungi, and the initial steps of its
production are regulated by trichodiene synthase enzyme
encoded by tri5 gene (Bowen and Rovira 1999; Cardoza et
al. 2011; Jain et al. 2013; Kumari et al. 2015; Malmierca et al.
2013). The protein involved in its transport is encoded by
tri12 gene that has been studied in Trichoderma spp. that
belong to major facilitator superfamily proteins showing
structural resemblance with drug efflux pumps (Chaudhary
et al. 2016; Sandhu and Akhter 2015). Harzianum A (HA) is
produced by Trichoderma arundinaceum and is reported to be
non-phytotoxic and observed to induce the expression of
PR1b1 and PR-P2 genes (defence-related genes) of salicylic
acid (SA) pathway and also reported to reduce the growth of
both Botrytis cinerea and Rhizoctonia solani (Malmierca et al.
2012). It was reported that DON represses the mycoparasitic
ability of Trichoderma spp. by reducing the expression of
chitinases and other degrading enzymes (Audenaert et al.
2013; Lutz et al. 2003), but Trichoderma spp. were also re-
ported to inhibit the growth of Fusarium spp. that produces
DON (Malmierca et al. 2012). It indicates that there must be
some unknown mechanism operating which not only sup-
presses the effect of DON but also results in inhibition of the
growth of the pathogenic fungi. It was also reported that DON
may take part in modifying the primary carbohydrate metab-
olism and the primary nitrogen metabolism of the plants sig-
nificantly (Warth et al. 2015). Metabolomic analysis showed
that two amino acids namely alanine and serine were less
abundant in wheat treated with DON, while in the same sam-
ples, those amino acids were observed to be more abundant
and have been associated with different plant defence mecha-
nisms (Warth et al. 2015). These were mostly aromatic amino
acids like phenylalanine, tyrosine and tryptophan which are
involved in the shikimate pathway. The aromatic secondary
metabolites (phenylpropanoids, tryptamine and tyramine) are
produced by the end products of this pathway. These aromatic
SMs serve as precursors for many defence-related compounds
such as aromatic amines and its hydroxycinnamic acid amide
conjugates with the plant hormone auxin (Warth et al. 2015).
The metabolomic studies performed until now are mainly on
the plants treated only with trichothecene compounds, while
there is a need to study this with the pathogenic fungi as well
as with the PGPF treatments to better understand the complex-
ity of rhizosphere microenvironment of the plant. It is reported
that at later stages of infection, DON inhibits the synthesis of
pathogen-related proteins, but some studies have shown that at
lower concentrations, it inhibits the programmed cell death
(PCD) by inducing the defence-related genes (Desmond et
al. 2008; Diamond et al. 2013). This dual effect of DON on
the defence system of the plant at various concentrations and
phases of pathogenesis shows that it may elicit some other
factors which cause this differential behaviour of DON.
Some of the probiotic strains of Bacillus and Lactobacillus
have shown the detoxifying potential against DON (Cheng
et al. 2010). DON is reported to bind with the A-site of the
peptidyl transferase centre of the eukaryotic ribosome which
is finally shown to lead to the inhibition of protein synthesis
(de Loubresse et al. 2014). It is reported that microbial cultures
isolated from farmland soil, cereal grains and other sources
transformed DON into simpler products (mainly 3-keto-4-
deoxynivalenol) (Popiel et al. 2008; Völkl et al. 2004), but
the enzymes involved in degradation of DON are yet to be
reported.
Macrotrichothecenes
The macrotrichothecenes are characterized by the presence of
cyclic diester or triester linkages at C-4 to C-15 positions [e.g.
satratoxins, verrucarins, roridins, myrotoxins (isolated from
fungi) and baccharinoids (isolated from Baccharis spp.)]
(McCormick et al. 2011) (Table 1). Verrucarin A belongs to
trilactone group (epoxytrichothecene dilactones and
trilactones) of trichothecenes. Antileukemic compounds were
derived from verrucarin A by the chemical modification at β-
9,10-epoxides (7 and 12, respectively) and using epoxidation
of the 9,10 double bond of the A ring (Jarvis et al. 1980). It is
reported that satratoxin G interactions with the ribosomal sub-
units precede apoptosis in macrophages and the apoptotic ef-
fect of satratoxin H is mediated through DNA double-stranded
break in cells (Nusuetrong et al. 2012). Not many studies are
available on these trichothecenes since they are not found in
the contaminated food.
Advantageous trichothecene molecules
Many of the trichothecene compounds are useful for plants as
well as animals. It is a well-established fact that some of the
trichothecenes fortify the defence system of the plants against
the pathogenic microbes and parasites. They were reported to
have bio-control activity and were also documented as poten-
tial candidates for bioherbicides (Hoagland et al. 2012;
Vidhyasekaran 2015). Some of these compounds were report-
ed to be novel anti-cancer and immunosuppressive agents in
allografts (Fig. 2) (Bae et al. 2015; Su et al. 2013).
Effects of trichothecene molecules on plant cells
Trichothecenes alter the expression of genes involved in var-
ious metabolic pathways which affect the host plant and in-
crease its ability to encounter the pathogenic soil microbes and
pests (Fig. 1). HA-induced expression of PR1b1 and PR-P2
genes has been reported to be involved in SA pathway. HA
has been purposed to be one of the microbe-assisted molecular
patterns (MAMP) (Hermosa et al. 2013). MAMP signalling
system in plants may generate specific Ca2+
or other secondary
Appl Microbiol Biotechnol
6. signal signatures in the cytosol, which may trigger pathogen
protecting responses like SA biosynthesis (Lecourieux et al.
2006; McAinsh and Pittman 2009; Vidhyasekaran 2015). HA
was observed to repress the expression of genes involved in the
production of botrydial and other virulence genes (atrB and
pg1) of B. cinerea. atrB of B. cinerea encodes for an ABC
transporter (protect against toxic compounds) and pg1 encodes
for endopolygalacturonase (involved in the cuticle and cell
wall degradation) (Malmierca et al. 2015). The complex
plant-microbe interactions occur between the SM produced
by PGPF, the host plant and the pathogenic fungi, but a zoom
out view of a working model/pathway based on the existing
body of available evidences that may explain these crosstalks,
which were still unknown. Trichodermin produced by
Trichoderma brevicompactum showed stronger inhibitory ef-
fect against mycelial growth of plant pathogenic fungi i.e.
Rhizoctonia solani and B. cinerea but relatively poor inhibitory
effects against Colletotrichum lindemuthianum (Shentu et al.
2014) (Fig. 3). DON was shown to induce the accumulation of
basic leucine zipper protein transcription factor (bZIP) and
reactive oxygen species (ROS) that has observed to lead the
induction of defence-related genes and suppression of pro-
grammed cell death at lower concentrations in the plants
(Desmond et al. 2008; Ansari et al. 2007). Some of the tricho-
thecenes may be a potential source of bioherbicides (Morin
et al. 2000; Amusa 2006). Roridin A, a trichothecene produced
by the fungus Myrothecium verrucaria, acts as bioherbicidal
on weeds like Pueraria lobata (kudzu) (Hoagland et al. 2012).
Further genomic and proteomic studies are needed to decipher
the underlying molecular mechanism of action of Roridin A
against the weed. Desjardins et al. (2007) reported that
NIV showed no phytotoxicity to Arabidopsis thaliana de-
tached leaves, whereas it was strongly phytotoxic to the intact
Lemna pausicostata plantlet. T-2 toxin has been found to be
nematicidal to Meloidogyne javanica, a nematode (Ciancio
and Bourijate 1995). Two trichothecene compounds
namely 4,15-diacetylnivalenol and DAS isolated from
Fusarium equiseti are shown to inhibit egg hatch of soybean
Gα of GPCR
Trichothecene
Differential expression?
Pattern recognition receptor
(PRR)?
SA synthesis
Ca2+
Calmodulins (CaMs)
and CaM-like proteins (CML)
Protein-ligand
interactions?
Unknown protein? +
Protein-protein interactions
PR1b1 PR-P2
?
Metaboliic pathway
Shikimate pathway
Trichothecene molecules
Fig. 2 Schematic presentation shows the interactions between SMs
and the plant cells: Some of the trichothecenes were purposed as
MAMPs which trigger the defence system of the plant by activating SA
pathway and also may elicit secondary signalling molecules like Ca2+
that
induces CaM/CML proteins which finally lead to the expression of
defence-related genes (Vidhyasekaran 2015). These compounds alter
the carbohydrate and nitrogen metabolism of the plant. Gα of GPCR
regulates the gene expression regulation mediated by these compounds
(Warth et al. 2015). All of the above showed that these compounds may
affect the plant cells at the gene levels, in basic metabolic pathways and
pathways of the defence systems
Appl Microbiol Biotechnol
7. cyst nematode as well as root-knot nematode and immobilized
second-stage juveniles in M. incognita (Nitao et al. 2001). As
many of the fungi occur in the rhizosphere of the plants and there
are few studies on the interactions of nematode-antagonistic
compounds, further investigation in this direction can be the first
step towards deciphering the role of trichothecenes produced by
plant growth promoting fungi to interfere in the normal devel-
opment of pathogenic (root-feeding) nematodes.
Effects of trichothecene molecules on animal cells
Trichothecene compounds were reported to exhibit potent
anti-tumour activity (Iida et al. 1996). Some of the trichothe-
cenes are reported to be the potential therapeutic candidates
for cancer treatment (Fig. 4). Trichothecene has been reported
to inhibit phosphorylation of 1κKβ and suppression of its
activation which finally turns off the expression of genes in-
volved in NF-κB signalling pathway, including XIAP, cyclin
D1 and Bcl-xL that regulate cell survival and cell proliferation.
This is reported to lead in cell cycle arrest and cancer cell
apoptosis without affecting normal cells with low basal
NF-κB activity (Su et al. 2013). Trichothecene was also ob-
served to exhibit potent inhibition activity against Epstein-
Barr virus early antigen (EBV-EA) activation induced by the
tumour promoter, 12-O-tetradecanoylphorbol-13-acetate
(TPA) (Konishi et al. 2003). Verrucarin A showed potential
activity to regulate the endoplasmic reticulum stress induced
by cancer cells by decreasing the gene expression of GRP78
(molecular chaperone), CHOP (stress‐inducible nuclear pro-
tein) and XBP-1(X-box-binding protein-1) which finally re-
sulted in reduced phosphorylation of IRE1α protein. As these
genes are involved in ER stress, verrucarin A is considered as
a potential candidate for therapeutic use in the cases involving
diabetes, obesity and disorders related to dysfunction of ER
stress (Bae et al. 2015). It was also reported that in DAS, the
acetate groups on C-15 along with that on C-4 positions are
PGPF
Pathogenic fungi
ROS
PR1b1
PR-P2
Virulent genes
(atrB and pg1)
Plant cell
ABC transporters, UDP-glucosyltransferases,
cytochrome P450s, and glutathione-S-
transferases
Metaboliic pathway
?
Detoxification?
Trichothecene receprtors, transporters and other
proteins involved in pathogenic fungi?
Three way crosstalk in the rhizosphere
Trichothecene
Trichothecene molecules
Virulence factor
(BOT)
Genes of tri cluster
PR1
PDF1.2
Fig. 3 Trichothecenes affect the tripartite PGPF-plant-pathogenic
fungi interactions in the niche of rhizosphere: These compounds
secreted by the PGPF are reported to alter the expression of virulent
genes of the pathogenic fungi, while their virulent factors are
responsible for the upregulation of the genes involved in the
biosynthetic pathway of some trichothecenes (Malmierca et al. 2015).
Simultaneously, trichothecene molecules secreted by the pathogenic fun-
gi have been recorded to alter the expression of different genes of meta-
bolic pathways of the plants that finally result in detoxification of these
compounds (Gardiner et al. 2010). This diagram shows the dynamic
behaviour of these compounds in the microcosm
Appl Microbiol Biotechnol
8. involved in anticancer activity (Nitao et al. 2001). Satratoxin
H and satratoxin G have been recently shown to induce apo-
ptosis in the PC-12 neuronal model (Bae et al. 2009; Islam
et al. 2008). Fusarenon X is reported to be immunosuppres-
sive molecule which is shown to reduce the anti-sheep red
blood cell (SRBC) antibody response and delay in the allo-
graft rejection time in mice (Masuda et al. 1982). T2 toxin was
shown to suppress the SRBC antibody response and delay in
the time of allograft rejection in mice (Masuda et al. 1982).
There is scope to develop these compounds as effective im-
munosuppressive agents by lowering their toxicity against
mammalian cells. This could be carried out by modifying
the functional groups present on these molecules while keep-
ing the core structure intact.
Disadvantageous trichothecene molecules
Trichothecenes produced by the pathogenic fungi are harmful
to the crops and animal cells that lead to the economic loss and
may affect human health (De Lucca 2007). Fusarium spp. are
one of the fungi that affect the crops worldwide, and trichothe-
cenes produced by them aid the fungi to invade the plants lead-
ing to oxidative stress and nitrogen starvation, and made them
better equipped to compete for food with plants. Trichothecenes
are classified as gastrointestinal toxins, dermatotoxins,
immunotoxins, hematotoxins and gene toxins (Nesic et al.
2014). Trichothecenes mediate their toxicity by inhibition of
protein, RNA, and DNA synthesis. Other toxic effects of tricho-
thecenes involve disruption of membrane transport and func-
tion, suppression of the immune response and abnormal blood
function effects (Hussein and Brasel 2001; Nesic et al. 2014).
Trichothecenes present in food as contaminant cause anorexia,
nausea, vomiting, headache, abdominal pain, diarrhoea, chills,
giddiness and convulsions (De Lucca 2007).
Negative effects on plants and lower eukaryotes
Trichothecenes produced by the pathogenic fungi are reported
to induce oxidative stress in plants. The peroxide stress stim-
ulates the production of the mycotoxins in the pathogenic
fungi (Ponts et al. 2007), a toxin with a demonstrated role in
Trichothecene molecules
MAP Kinase
ROS
Inhibition of protein, RNA
and DNA synthesis
Apoptosis
XIAP, cyclin D1 and Bcl-xL, GRP78, CHOP, XBP-1 and IRE1α
ER stressCancer cell
apoptosis
Fig. 4 Trichothecenes are toxic to the animal cells: The exposure of
these compounds leads to disproportionate generation of ROS in the cells
that may cause oxidative stress (Mishra et al. 2014; Sahu et al. 2008). The
interactions of the ribosomal subunits with these compounds could in-
duce apoptosis in macrophages, and the apoptotic effect is reported to be
mediated through DNA damage in the cells (Nusuetrong et al. 2012).
Some of them have shown promising results to be developed as anti-
cancer agents. These compounds may alter the expression of the genes
involved in the ER stress and apoptosis. These molecules were shown to
have potentials to be specifically targeted to the cancerous cells for ther-
apeutic interventions (Su et al. 2013; Bae et al. 2015)
Appl Microbiol Biotechnol
9. pathogenesis in wheat (Montibus et al. 2013). The ROS pro-
duced during oxidative stress stimulated programmed host
cell death supporting the fungal growth, whereas contrarily,
ROS may also trigger the induction of antimicrobial host de-
fence against the plant (Desmond et al. 2008). Further studies
are needed to modify the structure of DON to reduce its tox-
icity to the plants which may stimulate only the defence sys-
tem of the plant (Fig. 3). T-2 toxin was reported to affect the
permeability of cell membranes and causes changes in the
phospholipid turnover and lipid peroxidation (Bunner and
Morris 1988; Bouaziz et al. 2006; Ingle et al. 2009).
Trichothecene was shown to inhibit the mitochondrial trans-
lation in Saccharomyces cerevisiae (McLaughlin et al. 2009;
Bin-Umer et al. 2011). There is need to further investigate the
reported effects of various trichothecenes on mitochondria of
lower eukaryotes and determining how the pathogen itself
protects its own mitochondria from the deleterious effects of
these toxins (Bin-Umer et al. 2011).
Negative effects on animal cells
Trichothecene poisoning causes vomiting, diarrhoea, rejec-
tion of food, inflammation of the gastrointestinal tract, im-
pairment of nerve cells, heart muscle, lymphatic system,
testes and thymus, and formation of necrotic tissue and
may also cause alimentary toxic aleukia (ATA) (Bouaziz et
al. 2006; Ingle et al. 2009; Joffe 1978; Ndossi et al. 2012).
NIV present in the animal feed showed slight increase in
IgM levels, deregulated the production of IgA antibody
and reproduce to cause the development of IgA nephropa-
thy (Hinoshita et al. 1997; Rana et al. 2015; Sugita-Konishi
and Nakajima 2010). It was observed that the peptidyl trans-
ferase inhibition by trichothecene molecules may trigger a
ribotoxic stress response that activates c-Jun N-terminal ki-
nase (JNK)/p38 mitogen-activated protein kinases (Shifrin
and Anderson 1999). The activated kinases are important
transducers of downstream signalling events related to apo-
ptosis. It is reported that selected trichothecenes strongly
activate JNK/p38 kinases and induce rapid apoptosis in
Jurkat T cells (Merhej et al. 2011; Pestka et al. 2004;
Pestka and Amuzie 2008; Shifrin and Anderson 1999).
Cellular metabolism normally produces reactive oxygen
species [such as hydroxyl radicals and nitric oxide (ROS)]
by-products. While exposure to harmful compounds leads
to disproportionate generation of reactive oxygen species
poses a serious problem to bodily homeostasis and causes
oxidative tissue damage (Fig. 4). DON-induced cellular ox-
idative stress in rat liver by ROS generation has been report-
ed to cause hepatotoxicity (Mishra et al. 2014; Sahu et al.
2008). The ROS generation is observed to be capable of
oxidizing DNA bases that may adversely affect DNA struc-
ture (De Bont and Van Larebeke 2004; Islam and Pestka
2006; Le Drean et al. 2005; Mishra et al. 2014; Ueno et al.
1995; Yang et al. 2000). It is reported that NIV induces
oxidative stress and enhances pro-oxidative effect of DON
in an intestinal epithelial non-tumorigenic cell line (Del
Regno et al. 2015). It is also documented that trichothecene
molecules-induced oxidative stress could be mediated by
NADPH oxidase, calcium homeostasis alteration, NF-κB
and Nrf2 pathways activation and by iNOS and
nitrotyrosine formation (Del Regno et al. 2015). T-2 toxin-
induced oxidative stress is reported to activate various sig-
nalling pathways such as MAP kinases and caspases which
usually lead to apoptosis (Arunachalam and Doohan 2013).
T-2 toxin significantly was reported to alter the expression
of proteins involved in oxidative stress namely, glutathione-
S-transferase (GST), glutathione peroxidase (GPx), super-
oxide dismutase (SOD) and catalase. The altered expression
of anti-oxidant genes showed that oxidative stress can be
one of the mechanisms of T-2 toxin-mediated toxicity
(Chaudhary et al. 2009). The high dose of DON may affect
the activity of the aromatase enzyme that causes less pro-
duction of estradiol (Ranzenigo et al. 2008). The exposure
of DON, T-2 toxin and HT-2 toxin is showed to induce
adverse effects on the cell viability, steroidogenesis and al-
tered expression of genes involved in the reproductive sys-
tem (Ndossi et al. 2012). Therefore, trichothecenes may be
considered as potential endocrine disruptors.
Conclusions and future directions
Studies on the absolute stereochemistry and the dynamic
structural behaviour of the trichothecenes in different environ-
ments (in the water/cell) is required to accommodate the ac-
tivity of the different substituent functional groups in addition
to the core chemical structure of these molecules. Protein-
ligand structural studies may also help to understand the un-
derlying mechanisms for differences in toxicity among these
compounds (Garvey et al. 2008, 2009; Shank et al. 2011).
There is need to study the effects and modes of action of these
small molecules on the metabolic pathways dealing with bio-
chemical complex interactions in the host plants.
Trichothecenes have shown relatively few effects on bacterial
systems in comparison to eukaryotic organisms. There is need
to investigate these discriminatory toxic effects of trichothe-
cene molecules between prokaryotes and eukaryotes that re-
main to be seen, whether the toxicological resistance observed
for prokaryotic system is due to the differences in cellular
machinery, rapid metabolism or inefficient membrane translo-
cation (Shank et al. 2011). Further research will help to under-
stand whether HA could interact directly with the calmodulin-
binding proteins involved in the SA signalling of the plant
cells and the proteins involved in the upstream of this pathway
that finally result in the expression of the defence-related
genes. Some of the trichothecenes are reported to be the
Appl Microbiol Biotechnol
10. potential anti-cancer agents (Su et al. 2013), and further inves-
tigation of anti-tumour profiling will be able to establish them
as promising drug for future cancer therapy. Moreover, the
studies on these molecules focusing on mechanism of action
may provide other possible targets for the drugs. It is reported
that HA increases the expression of genes involved in the
defence system of the plant as well as decreases the expression
of genes related to virulence factors of the pathogenic fungi
(Malmierca et al. 2015). However, it is not clear, whether
other SMs produced by pathogenic fungi are able to regulate
or interfere with HA production in PGPF (Malmierca et al.
2015). It is reported that the mutualism between
Aphelenchoides saprophilus (Nematoda) and Folsomia
candida (Arthropoda) reduces the biomass of Fusarium
culmorum, the pathogenic fungi and the content of DON in
infected wheat plants (Wolfarth et al. 2013). The intermediate
products of the biosynthetic pathway of these compounds are
well established quorum-sensing molecules which may inter-
act with bacteria present in the rhizosphere (Xanthomonas
campestris, Pseudomonas aeruginosa, Burkholderia
cenocepacia and Streptococcus mutans) and could inhibit
their brimming ability and finally could reduce production of
anti-fungal compounds (Scherlach et al. 2013). There is need
of further studies on these small dynamic biosystems of the
soil (microcosm) comprising of the SM, PGPF, the pathogenic
microbes, the pathogenic nematodes and the host plant. It will
provide the overall cellular mechanism of action of these small
molecules on the biosystem as a whole and give insight for a
better understanding of their roles at molecular levels, tissue
levels and at organism levels. An integrated approach should
be applied to study the microcosm involving in vivo, in vitro
and in silico techniques using modern ‘omic’-based
bioanalytical technologies so that the complex interactions
between the organisms (the host, the microbes including sym-
bionts and pathogenic fungi and bacteria, and the nematodes)
could be revealed. The system scale metabolomic profiling
studies will help to understand the role of important com-
pounds (like precursors of the end product or common among
the organisms) in the crosstalks between the organisms, while
transcriptomics/proteomics in conjunction with in silico stud-
ies will help to understand the mechanism of action of these
compounds.
Acknowledgments University Grant Commission, Govt. of India
(UGC), is acknowledged for providing financial support in the form of
stipend to IK. Research in MA lab is supported by UGC and Science and
Engineering Research Board, DST, Govt. of India (SERB). Research in
YA lab is supported by extramural research funds from UGC and SERB.
Compliance with ethical standards All authors have jointly worked
on the manuscript and agree to its publication. No part of the manuscript
has been published previously. The acknowledgements contain complete
information on the funding we receive. This work does not involve hu-
man participants or animals.
Conflict of interest Authors declare that there is no conflict of interest.
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