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Abstract
a1111111111 Schistosomiasis,
AU : Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly:
a severe parasitic disease, is primarily caused by Schistosoma mansoni,
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Schistosoma japonicum, or Schistosoma haematobium. Currently, praziquantel is the only
recommended drug for human schistosome infection. However, the lack of efficacy of prazi-
quantel against juvenile worms and concerns about the emergence of drug resistance are
driving forces behind the research for an alternative medication. Schistosomes are obliga-
OPEN ACCESS
tory parasites that survive on nutrients obtained from their host. The ability of nutrient uptake
Citation: Zhu P, Wu K, Zhang C, Batool SS, Li A, Yu depends on their physiological structure. In short, the formation and maintenance of the
Z, et al. (2023) Advances in new target molecules
structure and nutrient supply are mutually reinforcing and interdependent. In this review, we
against schistosomiasis: A comprehensive
discussion of physiological structure and nutrient focus on the structural features of the tegument, esophagus, and intestine of schistosomes
intake. PLoS Pathog 19(7): e1011498. https://doi. and their roles in nutrient acquisition. Moreover, we introduce the significance and modes of
org/10.1371/journal.ppat.1011498
glucose, lipids, proteins, and amino acids intake in schistosomes. We linked the schisto-
Editor: Eva Gluenz, University of Bern: Universitat some structure and nutrient supply, introduced the currently emerging targets, and analyzed
Bern, SWITZERLAND
the current bottlenecks in the research and development of drugs and vaccines, in the hope
Published: July 27, 2023 of providing new strategies for the prevention and control of schistosomiasis.
Copyright: © 2023 Zhu et al. This is an open access
article distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in
any medium, provided the original author and 1. Introduction
source are credited.
Schistosomiasis is a major infectious disease worldwide that greatly endangers human health.
Funding: JH received funding support from the It is estimated to affect more than 250 million people and cause approximately 280,000 deaths
Natural Science Foundation of Hunan Province
annually [1]. Schistosoma mansoni (S. mansoni), Schistosoma japonicum (S. japonicum), and
(2023JJ30651) and the start-up funding for young
talents of Central South University (202045004).
Schistosoma haematobium (S. haematobium) are the major species that infect humans [2].
The funders had no role in study design, data Notably, different species of schistosomes can cause distinct symptoms and negative effects on
collection and analysis, decision to publish, or multiple human systems. Exposure to infested water is the primary cause of schistosome infec-
preparation of the manuscript. tion [3]. The cercaria in the water can rapidly penetrate human skin and then transform into
Competing interests: The authors declared no juvenile schistosome, namely schistosomula, which migrate through the vascular system until
conflict of interest. they reach the most suitable blood vessel for survival. Preferences for blood vessels vary among
schistosomes that accounts for difference of symptoms. Clinically, S. mansoni and S. japoni-
cum mainly cause gastrointestinal and hepatosplenic disorders, such as abdominal pain, enter-
itis, and hepatosplenomegaly. On the other hand, S. haematobium is associated with
genitourinary disorders, including hematuria, renal failure, squamous cell carcinoma of the
bladder, and organ lesions of the prostate, seminal vesicles, or cervix [4–6]. In humans, female
and male schistosomes develop and pair up as a prerequisite for egg production. Adult schisto-
somes living in the venous mesenteric, vesical plexuses, or other blood vessels lay hundreds of
eggs daily. The deposited eggs are the main cause of the pathological manifestations in
humans, leading to granulomatous reactions and subsequent chronic inflammation and fibro-
sis [6,7].
Anti-schistosomal drugs have been continuously developed, but most have been eliminated
due to significant side effects, high costs, or other reasons. For example, hycanthone was effec-
tive in killing S. mansoni and S. haematobium, but its hepatotoxicity and mutagenicity led to
its elimination [1]. The development of praziquantel (PZQ) is the greatest advancement in the
field of schistosomiasis treatment. Currently, PZQ is currently the drug of choice because it is
not only effective in killing the 3 aforementioned schistosomes, but also has good pharmaco-
logical properties and low cost [8]. PZQ, on the other hand, has been shown to be inefficient in
killing schistosomula, and its extensive use has been linked to parasite drug resistance [1,8,9].
Historically, vaccine administration has been ranked as the most cost-effective method of pre-
venting diseases caused by pathogens [10]. However, there is no schistosome vaccine available
for human use. Over the past few decades, more than 100 schistosome antigens have been
identified, but only a few candidates have entered human clinical trials [9]. One of the main
reasons for this phenomenon is the improper selection or limitation of the models used for
evaluation.
The development of drugs and vaccines should be based on a thorough understanding of
schistosome characteristics. Schistosomes are obligate parasites; they completely depend on
their hosts for growth and reproduction. In contrast to most other parasites, schistosomes feed
on host blood, obtaining nutrients such as red blood cells, plasma proteins, glucose, lipids, and
amino acids through their digestive tract or tegument [11]. For example, adult schistosomes
consume nearly 5 times their dry weight of glucose per day through glycolysis to meet their
energy requirements [12,13]. When glucose access is blocked, the survival and oviposition of
schistosome are compromised [14]. Additionally, lipids are also essential for their oviposition
[15]. The presence of large amounts of triglyceride suggests that schistosomes value this sub-
stance [16]. Moreover, proteins, amino acids, and even vitamins are also crucial for the vital
functions of schistosomes. Therefore, describing the morphology and function of the schisto-
some tegument, esophagus, and intestine, understanding the essential factors to form and
maintain these structures, and identifying the key factors that ensure their nutrition supply
could significantly advance the development of drugs and vaccines to combat schistosomiasis.
In this article, we review studies on the morphology and function of schistosome tegument and
digestive tract, which will greatly contribute to our overall understanding of this parasite. We further
discuss the mechanisms involved in the uptake and utilization of nutrients by schistosomes and
highlight some emerging targets that can block or inhibit this process. We aim to provide a direction
for in-depth research and development of effective clinical treatments for schistosomiasis.
Fig 1. Morphology of schistosome. (A) The general morphological structure of schistosomes. (B) Adult male worm
with well-developed tubercles (T) and tegumental ridges (TR) on the dorsal surface (D) (×2,047). Adapted from ref [23].
(C) SEM of the posterior esophageal lining of S. mansoni showing the luminal surface greatly extended to form thin
plates. (L, Esophageal lumen; LE, Leucocyte.) (D) TEM of the thin plates. A central double line (white arrows) is evident
in each plate and discoid bodies (black arrows) are numerous. Adapted from ref [32]. (E) TEM of the S. mansoni gut
epithelium. The cytoplasm of the syncytial gastrodermal epithelium (ga) is rich in the rough endoplasmic reticulum (rer)
and Golgi apparatus, typical of a cell synthesizing proteins and glycans for export. The luminal surface is extended by
numerous thin lamellae (l) 3–5 microns long. (s, erythrocyte stroma; g, pigment granule; d, lipid droplets). Adapted from
ref [11].
https://doi.org/10.1371/journal.ppat.1011498.g001
the ventral surface of the 3-week-old juvenile S. mansoni, oral and ventral suckers and a bore
exhibiting the beginning of the gynecophoral canal can be observed, while many folds can be
seen on the dorsal surface [23]. In adult males, oral and ventral suckers, gynecophoral canal,
and well-developed tubercles and tegumental ridges can be found [23] (Fig 1B). Schistosomes
attach to the vascular wall with suckers, and these folds increase the contact area between the
worm body and the host blood, which is conducive to nutrient intake.
The presence of multiple functional proteins on the tegument also confirms its important
role in nutrient acquisition [24]. So far, several dozen major proteins belonging to different
protein families have been identified, including enzymes, structural proteins, and some schis-
tosome-specific proteins whose functions are yet to be studied [25]. Among these proteins,
some are involved in or assist in the transport of nutrients across the tegument [21,26,27]. For
instance, schistosome glucose transporter protein 1 and 4 (SGTP1/4) contribute to glucose
intake [28,29]. In addition, enzymes like calpain on the tegument contribute to degrading host
blood clotting protein and impeding the formation of blood clots [30], ensuring that important
structures on the tegument are not covered. Moreover, upon entry into the mammalian host,
the tegument undergoes significant changes [31], suggesting that it would change in response
to different conditions to improve the ability of nutrient intake.
interacted with esophageal secretions [37]. In addition to erythrocytes, bound leukocytes can
also be observed in the posterior esophagus, which are damaged and destroyed to varying
degrees [32]. Studies based on cytology and gene expression also confirmed that the esoph-
ageal gland is the site of the initial processing of ingested blood cells [11,32,33,38].
Table 1. Enzymes in the intestinal tract of schistosome and their functions and inhibitors.
Protein Function Inhibitor Reference
Cathepsin B1 (SmCB1/Sm31) Degrades hemoglobin α and β chains; degrades the plasma E-64 and CA-074 methyl ester [111,131,132]
proteins such as albumin, IgG, and α-2 macroglobulin
Cathepsin L1 (SmCL1/SmCF) Degrades hemoglobin Peptidyl fluoromethyl ketones, vinyl sulphones, [133–136]
and epoxysuccinyl derivatives
SmCL2 Might contribute to ingested protein degradation Cystatins [44,132,137,138]
SmCL3 Hydrolyzes albumin and hemoglobin E-64 and K11777 [139,140]
Asparaginyl endopeptidase Acts as a protein processor, can trans-activate SmCB1 and Aza-peptide Michael acceptors and epoxide [111,141–143]
(SmAE/legumain /Sm32) SmCL1 to their mature catalytic forms inhibitors
Cathepsin D (SmCD/aspartic Plays an apical role in the digestion of hemoglobin Antibodies generated to lipid core peptides [47,144,145]
protease)
Superoxide dismutase Resists oxidation products and host cell responses Diethyldithiocarbamate and tetrathiomolybdate [52,53,146]
Saposin-like proteins Promotes lipid degradation and absorption Unknown [37,50]
https://doi.org/10.1371/journal.ppat.1011498.t001
change dramatically, including the reversible change from oxidative metabolism to glycolytic
metabolism depending on glucose concentration [55,56]. It was found that adult schistosomes
consume up to 20% of their dry weight of glucose per hour, with glycolysis as the primary met-
abolic pathway [57]. Glucose interruptions, it turns out, do affect the survival of worms [14].
The mechanisms by which schistosomes obtain glucose and the factors that may affect glucose
intake or regulate metabolism have been investigated to find potential intervention strategies.
Schistosomes may rely primarily on glucose transporters for glucose acquisition. Schisto-
some glucose transporter protein 1 (SGTP1) and SGTP4 play a major role in glucose intake
[58]. Both SGTP1 and SGTP4 are expressed in S. japonicum and S. mansoni; however, there is
no report on the expression of SGTP4 in S. haematobium [59,60]. SGTP1 is distributed in the
basement membrane and internal tissues and is expressed in the eggs, sporocyst, cercariae,
schistosomula, and adult worms; whereas SGTP4 appears to be located only in the apical mem-
brane of mammalian-stage parasites [29,58]. The distribution characteristic means that
SGTP4, which interacts with the host, is responsible for obtaining glucose from the host blood,
while SGTP1 transports free glucose into the interstitial fluids [28]. In both juvenile and adult
worms, the suppression of SGTP1 or SGTP4 will limit glucose intake, and a significantly
greater impairment is exhibited with both genes suppressed [14]. SGTP-suppressed worms
have significantly reduced viability in vivo, which further confirms the pathway and impor-
tance of glucose. To maximize glucose uptake during glucose deprivation, the parasite may
increase the levels of SGTP1 and SGTP4 [55].
The glucose transporters are indispensable in glucose uptake, but we also note that there
are multiple signaling pathways that may regulate this process. According to a new study, Akt
(also known as protein kinase B) is required for SGTP4 expression, and Akt inhibition could
reduce worm glucose uptake [61]. The role of insulin in facilitating glucose transport by glu-
cose carriers is well established, and the insulin pathway in schistosomes is similar to that of
other organisms [62]. Schistosome insulin receptors (IRs), located in the tegument, belong to
the large class of receptor tyrosine kinases and can bind to human insulin [63,64]. These IRs
can activate downstream signaling transduction of tyrosine kinases to regulate glucose uptake
after binding to insulin [65,66]. Mechanistically, insulin signaling pathway can activate the Akt
signal in worms, which in turn promotes the expression of glucose transporter proteins [61].
Taking S. japonicum insulin receptor 1/2 as an example, it has been confirmed that their sup-
pression can significantly reduce glucose intake, in turn negatively affecting parasitic growth
and development [66]. Studies have identified the site where IR1/2 binds to host insulin, sup-
porting the design of vaccines [67]. It should be noted that, in addition to host insulin,
schistosome IRs can also bind to the schistosome insulin-like peptide, thereby activating the
worm’s insulin pathway [68]. Further studies confirmed that vesicle-associated membrane
protein 2 (VAMP2) knockdown significantly affected the transcript levels of SGTP1, SGTP4,
and insulin receptors (IR1 and IR2) [69]. In female worms, vamp2 RNAi mainly caused a reduc-
tion in egg production [69], which may be influenced by impaired energy access in males [70].
Schistosomes are capable of aerobic glucose metabolism, but glycolysis is their primary
mode of energy acquisition in hosts. A number of key enzymes involved in the schistosome
glycolytic pathway have been identified, such as triose-phosphate isomerize [71] and glyceral-
dehyde-3P-dehydrogenase [72]. Recent studies revealed that AMP-activated protein kinase
(AMPK) plays a significant role in the regulation of larval viability and adult sugar metabolism
[12]. AMPK is conserved in all eukaryotes and is the main regulator of intracellular energy
metabolism and energy homeostasis [73,74]. AMPK may not be essential for adults, but it is
certain that it regulates adult worm glycogen synthesis, storage and utilization, ensuring the
survival of schistosomes in situations such as transient glucose deprivation [12]. Fructose-
1,6-bisphosphate aldolase (FBPA) plays a key role in glycolysis by converting fructose-
1,6-biphosphate into dihydroxyacetone phosphate and glyceraldehyde phosphate. It was sug-
gested that S. japonicum FBPA may enable the worm to obtain more metabolites and win the
nutrient competition with the host, due to its lower Km and higher enzymatic efficiency for
degrading fructose-1,6-biphosphate than host FBPA [75]. Unfortunately, the expression of
FBPA in S. mansoni and S. haematobium has not been reported.
As glucose is primary source of energy for schistosome, hence, current research focuses on
mode of glucose uptake used by parasite. Glucose intake can be limited or blocked by inhibit-
ing the expression of related molecules, blocking receptor–ligand interactions, or destroying
the morphological structure and function of the tegument.
3.2. Lipids
Lipids account for at least 1/4 of the dry weight of adult schistosomes, and worms must obtain
lipids from external sources to meet their needs [11]. It was found that males consume only
2.5% of their lipid content per day, while females consume up to 50%, suggesting that males
have a higher lipid storage capacity or females possess a higher ability to utilize or excrete lipids
[11]. Human plasma lipids include triglycerides, phospholipids, cholesterol and its esters, as
well as free fatty acids. The current understanding of the mechanism of lipid acquisition and
utilization by schistosomes is limited, and we speculate that plasma lipids and erythrocyte
membranes may be the main source.
Fatty acid is one of the essential lipids for schistosomes. The fatty acid-binding protein fam-
ily member of S. mansoni called Sm14 may play an important role in fatty acid acquisition
[76]. Fatty acid oxidation (FAO) has been reported to be critical for schistosome oviposition
[77,78]. It was found that inhibition of carnitine palmitoyl transferase 1, which catalyzes the
rate-limiting step of FAO, and loss of acyl CoA synthetase or acyl CoA dehydrogenase function
would significantly decrease the rate of oxygen consumption and egg production of schisto-
somes [77]. But some researchers have doubts about the idea because no direct evidence of
FAO has been observed in schistosomes, and the genes coding for FAO-related enzymes are
absent in S. mansoni genome [79]. Michiel and colleagues used 14C-labeled fatty acids to study
their metabolism in adult S. mansoni worm pairs, and the results showed that adult worms
have a limited ability to metabolize lipids, despite that they have a need to acquire fatty acids
[79]. In any case, different studies point to the absolute necessity of fatty acids for schistosome
spawning. Of note, arachidonic acid, a kind of fatty acid, was identified as an endoschistosomi-
cide [80].
Some tegument lipids have been found to modulate host immunity, thus keeping them-
selves safe from excessive damage. For example, lyso-phospholipids are abundant in S. man-
soni tegument, mainly eicosenoic acid (20:1)-containing lyso-phosphatidylserine and lyso-
phosphatidylethanolamine species [81]. It has been proposed that lyso-phosphatidylserine can
act on host dendritic cells, which differentiate T cells towards the Th2 and Treg phenotypes
[82]. When incubated with linoleic acid, schistosomes secrete eicosanoids, including hydro-
xyeicosatetraenoic acid (HETE), prostaglandin E2 (PGE2), and prostaglandin D2 (PGD2),
which suppress host immunity and benefit worm survival [83,84].
In general, lipids are one of the essential nutrients for schistosomes and are mainly used for
biosynthesis that ensures the worm’s oviposition and resistance to host immunity.
Fig 2. Intake and utilization of glucose, lipids, protein, and amino acids by schistosome. Schistosomes obtain
glucose, lipids, proteins, and amino acids from host blood for energy production and as substrates for the synthesis of
their own substances to ensure normal life activities such as growth, reproduction, and egg production. The dotted line
represents controversial or uncertain content at present. Created with BioRender.com.
https://doi.org/10.1371/journal.ppat.1011498.g002
Interestingly, schistosomes can cause metabolic alterations in their human host that facili-
tates their predation of nutrients. It was found that metabolite profiles associated with host
energy and purine metabolism changed significantly after a period of S. haematobium infec-
tion [92]. The parasite’s demand for energy and other substances increases host glycogenolysis,
gluconeogenesis, and fatty acid synthesis, stimulates host glycolysis, and leads to increased lev-
els of host ADP, AMP, G6P, and 3-PG, which correlate positively with the intensity of infec-
tion [92,93]. In addition, tegumental enzymes dephosphorylate host G6P, AMP, and ADP,
facilitating parasite in uptake of glucose and adenosine [94]. The plunder of host energy leads
to alterations in host metabolism, which in turn provides additional nutrients to schistosomes
to some extent. We believe that all infectious species of schistosomes cause alteration in host
metabolism, and blocking or reducing the nutrient intake by schistosomes is not only damag-
ing to the parasite but also reduces the degree of alteration in host metabolism, which may be a
positive feedback process.
In summary, the uptake of nutrients by schistosomes, whether through the tegument or the
digestive tract, is based on structure and various types of molecules. These nutrients not only
provide energy or substrates required for anabolism, but are also essential for maintaining the
structure and affecting host immunity. The importance of clarifying the mechanisms of nutrient
uptake and utilization for the elimination of schistosomes in the body cannot be overstated.
Table 2. The distribution and function of some important proteins and the effect after being inhibited.
Target Main distribution Possible functions Effect of being suppressed Reference
VAMP2 Tegument (S. japonicum) Mediates membrane fusion and maintains normal Tegument shedding and the oversized bulb- [69,97]
tegument morphology like structure formation
TSP-2 Tegument (S.mansoni, S. Acts as a scaffold for protein complex formation The tegument becomes thinner and forms [101–
japonicum, and S. haematobium) vacuoles 103,147]
MEG-4.1 Esophagus (S.mansoni and S. Involves in the processing of host cells May not be able to escape the host immune [32,107]
japonicum) response
FoxA Esophagus (S.mansoni) Maintains MEG-4.1 expression and ensures the Ablation of the esophageal gland [110]
esophageal gland cell differentiation
FTZ-F1 and Esophagus (S.mansoni) Maintains the integrity of the esophageal gland Progressively lose the ability to accumulate [108]
MEG-8.3 and head nutrient
HNF4 Intestine (S.mansoni, S. Contributes to the renewal of intestinal stem cells Reduced expression of gut markers, [114–
japonicum, and S. haematobium) and the formation of microvilli-like structures impairment of gut production, and feeding 116,148]
disorders
https://doi.org/10.1371/journal.ppat.1011498.t002
As a significant part of schistosomes, the normal tegument function is crucial to the survival of
the worm, and of course, it is also our target to kill schistosomes. S. mansoni, S. japonicum, and S.
haematobium have no obvious difference in the morphological characteristics of the tegument
and even some proteins have high homology, such as Sm-TSP-2, Sj-TSP-2, and Sh-TSP-2
[103,104]. It implies that drugs or vaccines designed for certain molecules of the tegument may
have similar killing effects on the 3 species, which greatly simplifies drug or vaccine development.
Fig 3. Functions of VAMP2, FoxA, and HNF4 in schistosome. (A) VAMP2 on the vesicle membrane pairs with t-SNAREs on the target membrane to form a
complex that drives membrane fusion for maintaining the stability of the apical tegument membrane and molecular transport, and to transfer SGTP4 on the
vesicle membrane to the tegument. (B) Esophageal gland plays an important role in the digestion of blood components such as B cells, leukocytes, erythrocytes,
and antibodies. FoxA expressed by esophageal gland cells (egc) and stem cells neighboring esophageal gland (eg) can promote the differentiation and
development of esophageal gland cells and the expression of MEG-4.1, which binds cells by binding to molecules on the surface of leucocytes. (C) Schematic
diagram of the influence of hnf4(RNAi) on the intestinal tract of schistosome. (SNARE, soluble N-ethylmaleimide sensitive factor attachment protein receptor;
v-SNARE, VAMP2 on the vesicle membrane; SNAP-25, synaptosomal-associated protein of 25 kDa; t-SNARE, syntaxin and SNAP25 on the target membrane).
https://doi.org/10.1371/journal.ppat.1011498.g003
expression of gut markers and impairment of gut production [115]. Transmission electron
microscopy reveals that hnf4 RNAi schistosome intestinal tissues, although present, have sig-
nificantly fewer microvillous-like structures in the lumen (Fig 3C). In terms of uptake and
digestion of erythrocytes, most hnf4 RNAi schistosomes failed to uptake or digest erythrocytes.
In addition, proteolytic enzyme expression was reduced in these schistosomes, and cathepsin
B activity was significantly lower [115]. Infection experiments revealed normal liver morphol-
ogy in mice receiving the hnf4 RNAi parasite, whereas a large number of egg-induced granulo-
mas were present in control group [115]. However, the role of HNF4 in the development and
maintenance of the schistosome gut remains unclear. In addition, it has been demonstrated
that HNF4 is an important conserved transcription factor for the brush border gene program
in organs including the intestine [116]. Loss of HNF4 in the mouse intestinal epithelium will
result in severe disruption of the brush border [116], and this may also be one of the reasons
for the apparent reduction of microvillus-like structures in hnf4 RNAi schistosomes.
Overall, the structural formation and maintenance of the schistosome tegument, esophagus,
and intestine, as well as their normal function, provide us with many potential targets. Struc-
tural destruction of schistosomes will undoubtedly affect their nutrient uptake, which in turn
will affect the structure and viability of the worm.
ignore the structural homology between the parasitic and human biomolecules to prevent
harmful effects on host.
At present, anti-helminthic drugs and vaccines are being designed and developed based on
these structures and related molecules. For instance, polypyridylruthenium (II) complexes can
inhibit acetylcholinesterase activity in the tegument, significantly impair glucose uptake capac-
ity, and are effective against schistosomula and adult schistosomes [120]. Back to the star drug
against schistosomes, PZQ, its anti-helminthic effect may be related to muscle paralysis and
tegument damage [121,122]. Artemisinin derivatives (artemether and artesunate) have a simi-
lar effect to PZQ, but they have a better killing effect on juvenile worms than adults [123], so
the combination of the 2 drugs definitely has a better therapeutic effect [124]. It is currently
hypothesized that artemisinin derivatives generate free radicals through heme-dependent
reduction, which in turn cause lethal damage to schistosomes through the alkylation of para-
sitic proteins [42,125]. Surprisingly, the intestinal tracts of schistosomes are severely damaged
after artemether treatment [126]. Another anti-schistosome drug candidate, dithiocarbamates,
was recently reported to be nontoxic to human cells in experiments [127]. According to
research findings, dithiocarbamates can damage the tegument, cause intestinal dilatation,
inhibit worm spawning, and reduce their pair stability and viability [127]. Research on the
schistosome vaccine is also a hot spot, and a systematic review has been made [9].
Killing or reduction in parasitic pathogenicity by structural destruction or inhibition of
nutrient uptake proves to be a promising therapy. But only a few candidates have made it to
human clinical trials. One of the reasons is the limitations of in vitro schistosome culture tech-
niques. Schistosomes grow well during in vitro culture and can be grown from the early schis-
tosomulum stage to the adult worm stage [128], but they have serious defects in reproduction.
The inability of in vitro-cultured schistosomes to lay eggs, which are crucial for pathogenicity
in human host, certainly hinders the development of drugs or vaccines. Another reason for
this situation may be the limitations of animal models. For successful outcomes, experts sug-
gested that vaccine should be tested on animal models preferably baboons [129].
Vaccine and drug development is time and resource intensive which could take decades for
successful outcomes. Taking the funding limitations for parasitic research into account, many
processes should be aforethought. In addition, data obtained through mouse-only model stud-
ies should be used with caution when designing clinical trial protocols [130]. In response to
this global parasitic disease, laboratories working on schistosomes worldwide should be
encouraged to work together to develop drugs and vaccines for the treatment and prevention
of schistosomiasis, taking into account the parasitic structure, nutrient uptake, and their vari-
ous life functions. Generally, we illustrated the structural basis and pathways of schistosome to
obtain nutrients and summarized the related emerging targets. We also summarized several
bottlenecks in this field in the hope of attracting professionals’ attention and promoting the
application of strategies that combine nutrient blocking and structural disruption.
Acknowledgments
We thank the other teachers and students who participated in the discussion of the manuscript
in Human Microbiome and Health Group and Department of Parasitology from Central
South University.
Author Contributions
Funding acquisition: Jing Huang.
Investigation: Peng Zhu, Kaijuan Wu.
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