Over the last decade, there has been accumulating evidence showing that signalling pathways are involved in extensive biological and physiological processes in the human blood fluke schistosomes, playing essential roles in environmental sensing, host penetration, growth, development, maturation, embryogenesis, tissue self-renewal and survival. Owing to the likelihood of resistance developing against praziquantel, the only drug currently available that is effective against all the human schistosome species, there is an urgent requirement for an alternative treatment, arguing for continuing research into novel or repurposed anti-schistosomal drugs. An increasing number of anticancer drugs are being developed which block abnormal signalling pathways, a feature that has stimulated interest in developing novel interventions against human schistosomiasis by targeting key cell signalling components. In this review, we discuss the functional characterization of signal transduction pathways in schistosomes and consider current challenges and future perspectives in this important area of research.

Introduction

Despite extensive efforts at control, the neglected disease of schistosomiasis afflicts more than 200 million individuals in 76 tropical and developing countries [1]. It is caused by three major clinically relevant species of blood flukes — Schistosoma mansoni, S. japonicum and S. haematobium. Infection with S. mansoni and S. japonicum results in hepatic and intestinal schistosomiasis, while S. haematobium infections result in urogenital schistosomiasis. The treatment of schistosomiasis is almost exclusively dependent on the long-term mass administration of the single available drug, praziquantel (PZQ), which has led to growing concerns about drug resistance [2]. No effective anti-schistosome vaccine is available.

Schistosomes are parasitic helminth worms which have a complex lifecycle, involving an intermediate host (aquatic snail) and a mammalian definitive host, as well as free-living swimming stages (cercariae and miracidia) [3]. In contrast with other trematodes, schistosomes are dioecious and sexual development in the female worm is dependent on constant pairing with the male, through exquisite mechanisms that are not well understood. A molecular ‘dialogue’ thus takes place not only between the parasite and environmental stimuli (signalling molecules from hosts, e.g. growth factors, neurotransmitters; light, and changes in osmolality and/or temperature during infection), but also between the male and female worms. Protein kinases (PKs) play key functional roles in signal transduction in controlling a broad range of biological processes such as cell growth, proliferation, metabolism, male–female interactions controlling oocyte, and vitelline cell differentiation and fertility [4,5], and are thus required to ensure schistosome survival and completion of their complex lifecycle. Understanding the process of signal transduction is an area that has stimulated particular interest by researchers aiming to develop novel interventions (i.e. drugs and vaccines) against human schistosomiasis [69]. Based on their structure, PKs can be classified into eukaryotic protein kinases (ePKs) and atypical protein kinases [10]. The recent deciphering of the genomes of S. mansoni and S. haematobium identified over 250 ePKs [7,11].

Functional characterization of signalling pathways in schistosomes

A broad range of methodologies have been used to explore cell signalling in schistosomes, including in silico reconstruction of signalling pathways using transcriptome and genome data [12,13]; functional prediction of pathway components by comparative genomics [5]; in situ hybridization using ‘smart’ phospho-specific antibodies [14]; yeast two/three hybrid screening [15,16]; and RNAi and chemical inhibition followed by the observation of phenotype changes [17,18]. Vaccine trials, using signalling components as candidate antigens followed by the evaluation of their protection efficacy, have also been undertaken [19]. The application of these approaches has unravelled functional roles for particular signalling pathways/components in schistosome biology (Figure 1) as follows:

  • (1) A variety of PKs have been found to be specifically or predominantly expressed in gonads and shown to be involved in the development of the reproductive system, gametogenesis, and/or egg production [20]. These kinases include polo-like kinases (SmPlk1 and SmSak), Src kinase (SmTK3), Syk kinase (SmTK4), Src/Fyn kinase (SmTK5), Src/Abl kinase (SmTK6) and Abl-like PKs (SmAbl1 and SmAbl2) [4,21], the receptor Ser/Thr (S/T) kinases (SmTβRI/II [22,23]), receptor tyrosine kinases [venus kinase receptors (VKRs)] [24,25], insulin receptors (IRs) [19], schistosome epidermal growth factor receptor (SER) [16], fibroblast growth factor receptors (FGFRs) [26], mitogen-activated protein kinase (MAPK) [27], and protein kinase A (PKA) [28] and protein kinase C (PKC) [29].

  • (2) An insulin signalling pathway participates in regulating glucose metabolism in schistosomes, playing a pivotal role in worm growth, development, and maturity [19,30,31].

  • (3) A FGF signalling pathway plays a key role in the maintenance of adult stem cells and proliferation of germinal cells [32,33].

  • (4) PKC and extracellular signal-regulated kinase (ERK) signalling potentially control the homeostasis of early schistosomula [34]; and modulation of the activities these two kinases affects schistosomule motility and phenotype, and reduces the survival rate of schistosomula.

  • (5) PKA signalling may mediate the response to host neurotransmitter stimuli by early stage schistosomula and adult worms, affecting parasite motility [14,35]. Also, PKA signalling has been suggested to be required for the regulation of cercarial viability and excretory processes [28,35].

  • (6) Sensory protein kinase signalling (involving PKC, ERK, and p38 MAPK) allows cercariae to respond to changes in light/temperature, and the presence of linoleic acid, and promotes host penetration [36]. In addition, p38 MAPK plays a role in regulating the ciliary beat in miracidia and in sporocyst differentiation [37,38].

  • (7) SmFes, a cytoplasmic tyrosine kinase in S. mansoni, may participate in the penetration of the miracidium larval stage into the snail intermediate host and help larval transformation after definitive host penetration [39].

Current challenges

Despite recent reports of key findings in the area of signal transduction in schistosomes, some challenges remain as are now described:

  • (1) The lack of an immortalized schistosome cell line means that molecular signalling experiments need to be carried out with whole intact schistosomes, worm lysates, and/or primary cells, i.e. neoblast-like cells, or using other eukaryotic expression systems (i.e. yeast, Xenopus oocytes, or mammalian cell-culture systems).

  • (2) ‘Smart’ phospho-specific antibodies have been used to detect the activation of pathway components after careful validation, but the approach has been limited to only a few schistosome ePKs [5]. The lack of commercial schistosome-specific antibodies against many of the components involved in cell signalling pathways represents another obstacle, although this could be potentially resolved by establishing a facility similar to the Malaria Research and Reference Reagent Resource Center (MR4) (https://www.beiresources.org/About/MR4.aspx) to provide a centralized resource for research reagents to the schistosomiasis scientific community.

  • (3) Although key new methodologies are available for dissecting the functional roles of signal pathway components in schistosomes, phenotypic changes observed or knockdown effects can be maintained only for a relatively short time and in particular developmental stages [17]. The CRISPR/Cas9 system has recently been adapted for genome editing in diverse organisms [40], including the human protozoan parasites Toxoplasma gondii, Plasmodium falciparum, Trypanosoma cruzi, and Leishmania spp. [41]. Compared with RNA interference, CRISPR–Cas9-mediated editing has the potential to achieve long-term heritable gene manipulation in schistosomes. However, the application of CRISPR in schistosomes is still in its infancy [42].

  • (4) Inhibitors are powerful tools in characterizing the functional roles of ePKs, but it is critical to interpret the data they generate due to specificity considerations, which is not only a problem in the context of distinguishing between parasite and host enzymes, but also the case that some inhibitors have differing effects on ePK activity in organisms as phylogenetically diverse as flatworms and mammals. Also, unexpected ectopic effects may emerge due to inhibitors acting promiscuously depending on the concentration used or the concentration reached in a tissue.

  • (5) Developing vaccines targeting receptor kinases (e.g. as transmission-blocking vaccines) represents a novel path for developing control interventions [43]. Many anti-schistosome vaccines have been tested using the laboratory mouse, but it has been argued recently that this model in vaccination/challenge trials may be unsuitable for assessing vaccine efficacy [44]. Evaluating other animal models for vaccine studies or using larger or natural hosts of schistosome infection (e.g. bovines or non-human primates) in vaccine trials will thus be important but challenging due to the substantial increases in cost, the limited availability of reagents for analyzing protective immune responses in these mammalian hosts, and ethical considerations.

  • (6) In regard to targeting cell signalling for anti-schistosome chemotherapy, in order to increase deleterious drug effects, studies of compounds targeting multiple kinases (given the redundancies in signalling pathways) [7] are warranted, but this approach may increase the risk of non-specificity and side effects.

  • (7) The most significant challenge currently preventing the development of a new anti-schistosome drug is the lack of a prospect of profit, which has reduced the enthusiasm of pharmaceutical companies to develop new compounds against this neglected group of parasites. However, the constant and widespread use of low doses of praziquantel in global mass preventive chemotherapy programmes for schistosomiasis in high prevalence endemic areas increases the threat of drug resistance developing [45], emphasizing the need to continue research into developing new and effective compounds.

Future perspectives

Future in-depth investigations of signalling pathways in vital Schistosoma cell types and/or tissues are clearly warranted. For example, a cohort of somatic stem cells, namely neoblast-like cells, have been isolated and identified in S. mansoni, and this group of cells can proliferate and differentiate into derivatives of multiple germ layers [32]. It has been shown that the fgf signalling pathway plays a key role in the maintenance of this cell population. Yet, detailed information of the signalling cascade in this pathway remains elusive. Also recently, it has been found that mechanical injury results in both cell death and neoblast proliferation at wound sites in S. mansoni [46]. The scenario that schistosome neoblasts sense and transduce injury signals and in turn modulate their behaviour to repair damaged tissues is still unclear. In addition, neuromuscular signalling, induced by biogenic amines (i.e. acetylcholine, serotonin, dopamine, and histamine), plays a pivotal role in mobility control and the schistosome pairing process [4751]. Exploring signal transduction processes linking neuroactive receptors in the neuronal system of schistosomes will be of considerable interest. In this context, previous studies have confirmed the involvement of PKC and PKA in neurotransmitter receptor/G-protein-mediated signal transduction in schistosomes [14,36].

Diverse functions of schistosome signalling pathways/components.

Figure 1.
Diverse functions of schistosome signalling pathways/components.

Functional implications of signalling pathways/components throughout different developmental stages of schistosomes.

Figure 1.
Diverse functions of schistosome signalling pathways/components.

Functional implications of signalling pathways/components throughout different developmental stages of schistosomes.

As key regulators mediating gene expression at the post-transcriptional level, miRNAs may serve as nodes in regulating signal pathways [52], adding a further layer of complexity to signal transduction. Although comprehensive miRNA expression has been profiled in various developmental stages or different sexes in schistosomes [53,54], the process of cross-talk between miRNAs and cell signalling pathways in schistosomes is still unclear, but some temporal cues have emerged based on a limited number of studies. For instance, the expression profile of sja-miR-124-3p during different development stages [55] and the localization of sma-miR-124a-3p in the cephalic ganglia and in the nerve chords of adult worm [56] indicate its potential involvement in regulating signal transduction in the schistosome nervous system. Recently, Zhu et al. [57] found that the male-biased expressed miRNAs, miR-8 and miR-3479, may regulate gene expression likely involved in the Wnt and TGF-β signalling pathways.

Many PK inhibitors, including those approved by the US Food and Drug Administration (FDA) for cancer treatment, show efficacy as potential anti-schistosome drugs [18,21]. In terms of disruption of egg laying and worm killing, promising results have been obtained in vitro with tyrphostin AG1024, which potentially targets IRs and VKRs [58], and Imatinib, which negatively affects the kinase activities of SmAbl1/2 and SmTK6 [59]. However, experiments in vivo resulted in a markedly different outcome with Imatinib as the blood components alpha-1-acid glycoprotein and serum albumin reduced its killing efficacy [59]. Nevertheless, by screening 114 anticancer compounds, Cowan and Keiser [60] identified two kinase inhibitors, trametinib and vandetanib, exhibiting moderate anti-schistosomal properties, based on in vivo assays [60]. Inhibition of schistosome kinase activity by an RNAi-based approach caused severe anti-worm effects, emphazising the importance of MAPK signalling for parasite survival in vivo [27]. Recently, 40 protein kinases, considered essential for parasite survival, have been prioritized as druggable targets in S. haematobium, including fibroblast growth factor receptor and insulin receptors [7]. Owing to the functional and structural conservation of the catalytic domains between parasite and human ePK orthologues, new breakthrough points may be achieved by designing novel and effective inhibitors that can target sequences close to, but not in the ATP site, unusual accessory domains present in some PKs, or PKs specific to invertebrates such as members of the VKR family [61].

Furthermore, more sensitive molecular tools for schistosomiasis diagnosis have been developed recently [62,63], which enables earlier detection of a schistosome infection. Developing effective drugs targeting and killing adolescent worms will not only prevent the development of chronic liver pathology (i.e. egg-induced granuloma formation and fibrosis), the main clinical outcomes of hepatic schistosomiasis caused by the entrapped eggs in the liver tissues, but also help block transmission of the disease. In this regard, promising results have been obtained with two mTOR (mammalian target of rapamycin)-targeting inhibitors, temsirolimus and sirolimus [64], which killed newly transformed schistosomula within 24–48 h [60].

Summary
  • Important advances have been made in understanding facets of cell signalling in the human blood flukes and the functional characterization of several schistosome PKs using integrated approaches.

  • Temporal cues highlight the potential for identifying new druggable and vaccine candidates critical for schistosome signalling transduction and parasite survival.

Abbreviations

     
  • ePKs

    eukaryotic protein kinases

  •  
  • ERK

    extracellular signal-regulated kinase

  •  
  • IRs

    insulin receptors

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • PKA

    protein kinase A

  •  
  • PKC

    protein kinase C

  •  
  • PKs

    protein kinases

  •  
  • VKR

    venus kinase receptor

Funding

We are grateful for the funding provided by an Australian Infectious Disease Research Centre Seed Grant and a Program Grant from the National Health and Medical Research Council (NHMRC) of Australia [APP1037304].

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

References

References
1
Gray
,
D.J.
,
Ross
,
A.G.
,
Li
,
Y.-S.
and
McManus
,
D.P.
(
2011
)
Diagnosis and management of schistosomiasis
.
BMJ
342
,
d2651
2
Doenhoff
,
M.J.
,
Kusel
,
J.R.
,
Coles
,
G.C.
and
Cioli
,
D.
(
2002
)
Resistance of Schistosoma mansoni to praziquantel: is there a problem?
Trans. R. Soc. Trop. Med. Hyg.
96
,
465
469
3
Cai
,
P.
,
Liu
,
S.
,
Piao
,
X.
,
Hou
,
N.
,
You
,
H.
,
McManus
,
D.P.
et al. 
(
2017
)
A next-generation microarray further reveals stage-enriched gene expression pattern in the blood fluke Schistosoma japonicum
.
Parasit. Vectors
10
,
19
4
Beckmann
,
S.
,
Quack
,
T.
,
Burmeister
,
C.
,
Buro
,
C.
,
Long
,
T.
,
Dissous
,
C.
et al. 
(
2010
)
Schistosoma mansoni: signal transduction processes during the development of the reproductive organs
.
Parasitology
137
,
497
520
5
Walker
,
A.J.
,
Ressurreição
,
M.
and
Rothermel
,
R.
(
2014
)
Exploring the function of protein kinases in schistosomes: perspectives from the laboratory and from comparative genomics
.
Front. Genet.
5
,
229
6
You
,
H.
,
Gobert
,
G.N.
,
Jones
,
M.K.
,
Zhang
,
W.
and
McManus
,
D.P.
(
2011
)
Signalling pathways and the host-parasite relationship: putative targets for control interventions against schistosomiasis: signalling pathways and future anti-schistosome therapies
.
BioEssays
33
,
203
214
7
Stroehlein
,
A.J.
,
Young
,
N.D.
,
Jex
,
A.R.
,
Sternberg
,
P.W.
,
Tan
,
P.
,
Boag
,
P.R.
et al. 
(
2016
)
Defining the Schistosoma haematobium kinome enables the prediction of essential kinases as anti-schistosome drug targets
.
Sci. Rep.
5
,
17759
8
Gelmedin
,
V.
,
Dissous
,
C.
and
Grevelding
,
C.G.
(
2015
)
Re-positioning protein-kinase inhibitors against schistosomiasis
.
Fut. Med. Chem.
7
,
737
752
9
Morel
,
M.
,
Vanderstraete
,
M.
,
Cailliau
,
K.
,
Lescuyer
,
A.
,
Lancelot
,
J.
and
Dissous
,
C.
(
2014
)
Compound library screening identified Akt/PKB kinase pathway inhibitors as potential key molecules for the development of new chemotherapeutics against schistosomiasis
.
Int. J. Parasitol. Drugs Drug Resist.
4
,
256
266
10
Manning
,
G.
,
Whyte
,
D.B.
,
Martinez
,
R.
,
Hunter
,
T.
and
Sudarsanam
,
S.
(
2002
)
The protein kinase complement of the human genome
.
Science
298
,
1912
1934
11
Andrade
,
L.F.
,
Nahum
,
L.A.
,
Avelar
,
L.G.
,
Silva
,
L.L.
,
Zerlotini
,
A.
,
Ruiz
,
J.C.
et al. 
(
2011
)
Eukaryotic protein kinases (ePKs) of the helminth parasite Schistosoma mansoni
.
BMC Genomics
12
,
215
12
Zhou
,
Y.
,
Zheng
,
H.
,
Chen
,
Y.
,
Zhang
,
L.
,
Wang
,
K.
,
Guo
,
J.
et al. 
(
2009
)
The Schistosoma japonicum genome reveals features of host–parasite interplay
.
Nature
460
,
345
351
13
Berriman
,
M.
,
Haas
,
B.J.
,
LoVerde
,
P.T.
,
Wilson
,
R.A.
,
Dillon
,
G.P.
,
Cerqueira
,
G.C.
et al. 
(
2009
)
The genome of the blood fluke Schistosoma mansoni
.
Nature
460
,
352
358
14
de Saram
,
P.S.
,
Ressurreição
,
M.
,
Davies
,
A.J.
,
Rollinson
,
D.
,
Emery
,
A.M.
and
Walker
,
A.J.
(
2013
)
Functional mapping of protein kinase A reveals its importance in adult Schistosoma mansoni motor activity
.
PLoS Negl. Trop. Dis.
7
,
e1988
15
Beckmann
,
S.
,
Buro
,
C.
,
Dissous
,
C.
,
Hirzmann
,
J.
and
Grevelding
,
C.G.
(
2010
)
The Syk kinase SmTK4 of Schistosoma mansoni is involved in the regulation of spermatogenesis and oogenesis
.
PLoS Pathog.
6
,
e1000769
16
Buro
,
C.
,
Burmeister
,
C.
,
Quack
,
T.
and
Grevelding
,
C.G.
(
2017
)
Identification and first characterization of SmEps8, a potential interaction partner of SmTK3 and SER transcribed in the gonads of Schistosoma mansoni
.
Exp. Parasitol.
180
,
55
63
17
Guidi
,
A.
,
Mansour
,
N.R.
,
Paveley
,
R.A.
,
Carruthers
,
I.M.
,
Besnard
,
J.
,
Hopkins
,
A.L.
et al. 
(
2015
)
Application of RNAi to genomic drug target validation in schistosomes
.
PLoS Negl. Trop. Dis.
9
,
e0003801
18
Beckmann
,
S.
,
Leutner
,
S.
,
Gouignard
,
N.
,
Dissous
,
C.
and
Grevelding
,
C.G.
(
2012
)
Protein kinases as potential targets for novel anti-schistosomal strategies
.
Curr. Pharm. Des.
18
,
3579
3594
PMID:
[PubMed]
19
You
,
H.
,
Gobert
,
G.N.
,
Cai
,
P.
,
Mou
,
R.
,
Nawaratna
,
S.
,
Fang
,
G.
et al. 
(
2015
)
Suppression of the insulin receptors in adult Schistosoma japonicum impacts on parasite growth and development: further evidence of vaccine potential
.
PLoS Negl. Trop. Dis.
9
,
e0003730
20
Morel
,
M.
,
Vanderstraete
,
M.
,
Hahnel
,
S.
,
Grevelding
,
C.G.
and
Dissous
,
C.
(
2014
)
Receptor tyrosine kinases and schistosome reproduction: new targets for chemotherapy
.
Front. Genet.
5
,
238
21
Dissous
,
C.
and
Grevelding
,
C.G.
(
2011
)
Piggy-backing the concept of cancer drugs for schistosomiasis treatment: a tangible perspective?
Trends Parasitol.
27
,
59
66
22
Freitas
,
T.C.
,
Jung
,
E.
and
Pearce
,
E.J.
(
2007
)
TGF-β signaling controls embryo development in the parasitic flatworm Schistosoma mansoni
.
PLoS Pathog.
3
,
e52
23
Osman
,
A.
,
Niles
,
E.G.
,
Verjovski-Almeida
,
S.
and
LoVerde
,
P.T.
(
2006
)
Schistosoma mansoni TGF-β receptor II: role in host ligand-induced regulation of a schistosome target gene
.
PLoS Pathog.
2
,
e54
24
Gelmedin
,
V.
,
Morel
,
M.
,
Hahnel
,
S.
,
Cailliau
,
K.
,
Dissous
,
C.
and
Grevelding
,
C.G.
(
2017
)
Evidence for integrin - Venus kinase receptor 1 alliance in the ovary of Schistosoma mansoni females controlling cell survival
.
PLoS Pathog.
13
,
e1006147
25
Vanderstraete
,
M.
,
Gouignard
,
N.
,
Cailliau
,
K.
,
Morel
,
M.
,
Hahnel
,
S.
,
Leutner
,
S.
et al. 
(
2014
)
Venus kinase receptors control reproduction in the platyhelminth parasite Schistosoma mansoni
.
PLoS Pathog.
10
,
e1004138
26
Hahnel
,
S.
,
Quack
,
T.
,
Parker-Manuel
,
S.J
,
Lu
,
Z.
,
Vanderstraete
,
M.
,
Morel
,
M.
et al. 
(
2014
)
Gonad RNA-specific qRT-PCR analyses identify genes with potential functions in schistosome reproduction such as SmFz1 and SmFGFRs
.
Front. Genet.
5
,
a000505
27
de Andrade
,
L.F.
,
de Mourao
,
M.M.
,
Geraldo
,
J.A.
,
Coelho
,
F.S.
,
Silva
,
L.L.
,
Neves
,
R.H.
et al. 
(
2014
)
Regulation of Schistosoma mansoni development and reproduction by the mitogen-activated protein kinase signaling pathway
.
PLoS Negl. Trop. Dis.
8
,
e2949
28
Swierczewski
,
B.E.
and
Davies
,
S.J.
(
2010
)
Developmental regulation of protein kinase A expression and activity in Schistosoma mansoni
.
Int. J. Parasitol.
40
,
929
935
29
Ressurreição
,
M.
,
De Saram
,
P.
,
Kirk
,
R.S.
,
Rollinson
,
D.
,
Emery
,
A.M.
,
Page
,
N.M.
et al. 
(
2014
)
Protein kinase C and extracellular signal-regulated kinase regulate movement, attachment, pairing and egg release in Schistosoma mansoni
.
PLoS Negl. Trop. Dis.
8
,
e2924
30
Ahier
,
A.
,
Khayath
,
N.
,
Vicogne
,
J.
and
Dissous
,
C.
(
2008
)
Insulin receptors and glucose uptake in the human parasite Schistosoma mansoni
.
Parasite
15
,
573
579
31
Du
,
X.
,
McManus
,
D.P.
,
Cai
,
P.
,
Hu
,
W.
and
You
,
H.
(
2017
)
Identification and functional characterisation of a Schistosoma japonicum insulin-like peptide
.
Parasit. Vectors
10
,
181
32
Collins
, III,
J.J.
,
Wang
,
B.
,
Lambrus
,
B.G.
,
Tharp
,
M.E.
,
Iyer
,
H.
and
Newmark
,
P.A.
(
2013
)
Adult somatic stem cells in the human parasite Schistosoma mansoni
.
Nature
494
,
476
479
33
Wang
, III,
B.
,
Collins
,
J.J.
and
Newmark
,
P.A.
(
2013
)
Functional genomic characterization of neoblast-like stem cells in larval Schistosoma mansoni
.
eLife
2
,
e00768
34
Ressurreição
,
M.
,
Elbeyioglu
,
F.
,
Kirk
,
R.S.
,
Rollinson
,
D.
,
Emery
,
A.M.
,
Page
,
N.M.
et al. 
(
2016
)
Molecular characterization of host-parasite cell signalling in Schistosoma mansoni during early development
.
Sci. Rep.
6
,
35614
35
Hirst
,
N.L.
,
Lawton
,
S.P.
and
Walker
,
A.J.
(
2016
)
Protein kinase A signalling in Schistosoma mansoni cercariae and schistosomules
.
Int. J. Parasitol.
46
,
425
437
36
Ressurreição
,
M.
,
Kirk
,
R.S.
,
Rollinson
,
D.
,
Emery
,
A.M.
,
Page
,
N.M.
and
Walker
,
A.J.
(
2015
)
Sensory protein kinase signaling in Schistosoma mansoni cercariae: host location and invasion
.
J. Infect. Dis.
212
,
1787
1797
37
Ressurreição
,
M.
,
Rollinson
,
D.
,
Emery
,
A.M.
and
Walker
,
A.J.
(
2011
)
A role for p38 mitogen-activated protein kinase in early post-embryonic development of Schistosoma mansoni
.
Mol. Biochem. Parasitol.
180
,
51
55
38
Ressurreição
,
M.
,
Rollinson
,
D.
,
Emery
,
A.M.
and
Walker
,
A.J.
(
2011
)
A role for p38 MAPK in the regulation of ciliary motion in a eukaryote
.
BMC Cell Biol.
12
,
6
39
Bahia
,
D.
,
Mortara
,
R.A.
,
Kusel
,
J.R.
,
Andrade
,
L.F.
,
Ludolf
,
F.
,
Kuser
,
P.R.
et al. 
(
2007
)
Schistosoma mansoni: expression of Fes-like tyrosine kinase SmFes in the tegument and terebratorium suggests its involvement in host penetration
.
Exp. Parasitol.
116
,
225
232
40
Doudna
,
J.A.
and
Charpentier
,
E.
(
2014
)
Genome editing. The new frontier of genome engineering with CRISPR-Cas9
.
Science
346
,
1258096
41
Zhang
,
W.W.
and
Matlashewski
,
G.
(
2015
)
CRISPR-Cas9-Mediated genome editing in leishmania donovani
.
MBio
6
,
e00861-15
42
Cai
,
P.
,
Gobert
,
G.N.
,
You
,
H.
and
McManus
,
D.P.
(
2016
)
The Tao survivorship of schistosomes: implications for schistosomiasis control
.
Int. J. Parasitol.
46
,
453
463
43
You
,
H.
,
Gobert
,
G.N.
,
Duke
,
M.G.
,
Zhang
,
W.
,
Li
,
Y.
,
Jones
,
M.K.
et al. 
(
2012
)
The insulin receptor is a transmission blocking veterinary vaccine target for zoonotic Schistosoma japonicum
.
Int. J. Parasitol.
42
,
801
807
44
Wilson
,
R.A.
,
Li
,
X.-H.
and
Castro-Borges
,
W.
(
2016
)
Do schistosome vaccine trials in mice have an intrinsic flaw that generates spurious protection data?
Parasit. Vectors
9
,
89
45
Olveda
,
D.U.
,
Inobaya
,
M.T.
,
McManus
,
D.P.
,
Olveda
,
R.M.
,
Vinluan
,
M.L.
,
Ng
,
S.-K.
et al. 
(
2017
)
Biennial versus annual treatment for schistosomiasis and its impact on liver morbidity
.
Int. J. Infect. Dis.
54
,
145
149
46
Collins
,
J.N.R.
and
Collins
, III,
J.J.
(
2016
)
Tissue degeneration following loss of Schistosoma mansoni cbp1 is associated with increased stem cell proliferation and parasite death in vivo
.
PLoS Pathog.
12
,
e1005963
47
Wang
,
J.
,
Yu
,
Y.
,
Shen
,
H.
,
Qing
,
T.
,
Zheng
,
Y.
,
Li
,
Q.
et al. 
(
2017
)
Dynamic transcriptomes identify biogenic amines and insect-like hormonal regulation for mediating reproduction in Schistosoma japonicum
.
Nat. Commun.
8
,
14693
48
Ribeiro
,
P.
and
Patocka
,
N.
(
2013
)
Neurotransmitter transporters in schistosomes: structure, function and prospects for drug discovery
.
Parasitol. Int.
62
,
629
638
49
Ribeiro
,
P.
,
Gupta
,
V.
and
El-Sakkary
,
N.
(
2012
)
Biogenic amines and the control of neuromuscular signaling in schistosomes
.
Invert. Neurosci.
12
,
13
28
50
Leutner
,
S.
,
Oliveira
,
K.C.
,
Rotter
,
B.
,
Beckmann
,
S.
,
Buro
,
C.
,
Hahnel
,
S.
et al. 
(
2013
)
Combinatory microarray and SuperSAGE analyses identify pairing-dependently transcribed genes in Schistosoma mansoni males, including follistatin
.
PLoS Negl. Trop. Dis.
7
,
e2532
51
Lu
,
Z.
,
Sessler
,
F.
,
Holroyd
,
N.
,
Hahnel
,
S.
,
Quack
,
T.
,
Berriman
,
M.
et al. 
(
2016
)
Schistosome sex matters: a deep view into gonad-specific and pairing-dependent transcriptomes reveals a complex gender interplay
.
Sci. Rep.
6
,
31150
52
Inui
,
M.
,
Martello
,
G.
and
Piccolo
,
S.
(
2010
)
MicroRNA control of signal transduction
.
Nat. Rev. Mol. Cell Biol.
11
,
252
263
53
Cai
,
P.
,
Hou
,
N.
,
Piao
,
X.
,
Liu
,
S.
,
Liu
,
H.
,
Yang
,
F.
et al. 
(
2011
)
Profiles of small non-coding RNAs in Schistosoma japonicum during development
.
PLoS Negl. Trop. Dis.
5
,
e1256
54
Cai
,
P.
,
Piao
,
X.
,
Hao
,
L.
,
Liu
,
S.
,
Hou
,
N.
,
Wang
,
H.
et al. 
(
2013
)
A deep analysis of the small non-coding RNA population in Schistosoma japonicum eggs
.
PLoS ONE
8
,
e64003
55
Cai
,
P.
,
Gobert
,
G.N.
and
McManus
,
D.P.
(
2016
)
MicroRNAs in parasitic helminthiases: current status and future perspectives
.
Trends Parasitol.
32
,
71
86
56
Protasio
,
A.V.
,
van Dongen
,
S.
,
Collins
,
J.
,
Quintais
,
L.
,
Ribeiro
,
D.M.
,
Sessler
,
F.
et al. 
(
2017
)
MiR-277/4989 regulate transcriptional landscape during juvenile to adult transition in the parasitic helminth Schistosoma mansoni
.
PLoS Negl. Trop. Dis.
11
,
e0005559
57
Zhu
,
L.
,
Zhao
,
J.
,
Wang
,
J.
,
Hu
,
C.
,
Peng
,
J.
,
Luo
,
R.
et al. 
(
2016
)
MicroRNAs are involved in the regulation of ovary development in the pathogenic blood fluke Schistosoma japonicum
.
PLoS Pathog.
12
,
e1005423
58
Vanderstraete
,
M.
,
Gouignard
,
N.
,
Cailliau
,
K.
,
Morel
,
M.
,
Lancelot
,
J.
,
Bodart
,
J.-F.
et al. 
(
2013
)
Dual targeting of insulin and venus kinase receptors of Schistosoma mansoni for novel anti-schistosome therapy
.
PLoS Negl. Trop. Dis.
7
,
e2226
59
Beckmann
,
S.
,
Long
,
T.
,
Scheld
,
C.
,
Geyer
,
R.
,
Caffrey
,
C.R.
and
Grevelding
,
C.G.
(
2014
)
Serum albumin and α-1 acid glycoprotein impede the killing of Schistosoma mansoni by the tyrosine kinase inhibitor imatinib
.
Int. J. Parasitol. Drugs Drug. Resist.
4
,
287
295
60
Cowan
,
N.
and
Keiser
,
J.
(
2015
)
Repurposing of anticancer drugs: in vitro and in vivo activities against Schistosoma mansoni
.
Parasit. Vectors
8
,
417
61
Ahier
,
A.
,
Rondard
,
P.
,
Gouignard
,
N.
,
Khayath
,
N.
,
Huang
,
S.
,
Trolet
,
J.
et al. 
(
2009
)
A new family of receptor tyrosine kinases with a venus flytrap binding domain in insects and other invertebrates activated by aminoacids
.
PLoS ONE
4
,
e5651
62
Weerakoon
,
K.G.A.D.
,
Gobert
,
G.N.
,
Cai
,
P.
and
McManus
,
D.P.
(
2015
)
Advances in the diagnosis of human schistosomiasis
.
Clin. Microbiol. Rev.
28
,
939
967
63
Cai
,
P.
,
Weerakoon
,
K.G.
,
Mu
,
Y.
,
Olveda
,
D.U.
,
Piao
,
X.
,
Liu
,
S.
et al. 
(
2017
)
A parallel comparison of antigen candidates for development of an optimized serological diagnosis of schistosomiasis japonica in the Philippines
.
EBioMedicine
24
,
237
246
64
Ballou
,
L.M.
and
Lin
,
R.Z.
(
2008
)
Rapamycin and mTOR kinase inhibitors
.
J. Chem. Biol.
1
,
27
36