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Russell Kabir
Schistosoma japonicum, Schistosomiasis, Katayama Syndrome, and Molecular Conjecture
Schistosoma japonicum is a blood fluke that parasitizes mammalian hosts, specifically
Asian populations of humans and bovines. Flatworms of the genus Schistosoma cause
schistosomiasis, a chronic disease that afflicts more than 200 million people worldwide and
accounts for hundreds of thousands of deaths per year (Zhou et al. 2009). According to the WHO,
schistosomiasis contributes to the loss of 1.532 million disability-adjusted life years (DALYs)
(Gryseels 2006) and is one of ten tropical diseases targeted for control by global public health
organizations. This trematode causes an acute form of the disease known as Katayama syndrome,
which is an early clinical manifestation of schistosomiasis that occurs many weeks after infection.
The syndrome, previously known as Katayama fever, is primarily diagnosed in travelers and
“adventure tourists,” likely due to a lack of health care infrastructure and subsequent relative
immunity found in indigents of endemic areas (Ross et al. 2007). Climate change and floods are
being attributed to a reemergence of schistosomiasis in China, which has prompted a search for
sustainable, novel treatments and preventative measures, such as the antimalarial drug artemether,
and the development of a transmission blocking vaccine for reservoir hosts and humans
(Bottieau et al. 2005, Ingram 2002). Schistosoma japonicum is the first lophotrochozoan to have
a sequenced genome, which has resulted in a battery of conjectural conclusions about the
molecular constitution and evolutionary history of the parasite, as well as opportunities for new
interventions toward its control and elimination (Zhou et al.2009).
Schistosomiasis, and its associated host-parasite system, has plagued mankind for
millennia, first appearing in papyri from Pharaonic Egypt and human remains from ancient
China (Zhou et al.2009). Schistosoma japonicum is one of many different species of related
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blood-dwelling trematodes, but is not host-specific, allowing it to infect a variety of mammalian
definitive hosts like humans, canines, felines, and bovines (Combes 2005). The worms undergo a
complex life cycle, where adult males and females produce eggs in the superior mesenteric veins
of the small intestine. These eggs circulate to the liver, are shed in stools, and hatch in feces,
releasing miracidia. In freshwater, these motile miracidia swim and penetrate their specific snail
intermediate hosts, going through stages as sporocysts and then producing cercariae. These
cercariae are released from infected snails in response to sunlight after around 30 days, and swim
with their forked tail toward the skin of a mammalian host within 12-24 hours upon emerging
from the snail. The cercariae penetrate the host’s skin mechanically and through the production
of proteolytic enzymes. Once inside, they shed their tails to become schistosomula and invade
the lymphatic system, residing in the lungs before re-entering the circulatory system. The
schistosomula are carried to the portal blood of the liver, where they mature into adults, form
mating pairs, and migrate to the mesenteric venules of the bowel (Ross et al. 2007).
Schistosoma japonicum is specifically responsible for intestinal schistosomiasis due to
the location of its resident adult parasites within the large bowel. The adult’s eggs make their
way through intestinal walls and cause inflammation, lesions, and microulcerations. (Gryseels
2006). Symptoms include abdominal pain and discomfort, loss of appetite, and bloody diarrhea.
The “gold standard” for diagnosis is the analysis of excreta for eggs using fecal smears and the
Kato-Katz technique (Gryseels 2006). The penetration of the cercariae into human skin also
causes an urticarial rash. Adult worms can even cause neurological disease when they aberrantly
migrate to the brain or spinal cord (Ross et al. 2007). The frequency of these symptoms is
generally tied to the intensity of the infection in chronic schistosomiasis caused by the parasite,
but worm burden is poorly correlated with disease severity in acute schistosomiasis, or Katayama
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syndrome (Bottieau et al. 2005). This indicates that parasite load may not be as important as
parasite virulence when considering the appropriate course of action. Acute schistosomiasis is
one of the diseases onset by S. japonicum with the greatest prevalence in literature.
Katayama syndrome is associated with the clinical manifestations of schistosomiasis –
named for the district of Hiroshima, Japan, where it was once endemic and first described a
hundred years ago – and historically linked to the discovery and nomenclature of S. japonicum
(Bottieau et al. 2005, Ross et al. 2007). It is the imported form of schistosomiasis, and the one
most likely for physicians in non-endemic countries to diagnose improperly due its temporal
delay and nonspecific presentation. These symptoms are typically nocturnal fever, cough,
myalgia, headache, and abdominal tenderness (Ross et al. 2007).
There are various treatments for the complications associated with S. japonicum. Early
studies showed that motor oil and Vaseline provided some protection against urticarial infections,
but barrier creams containing the chemical dimethicone have been found to more effectively
prevent this rash than those without formulation (Ingram 2002). The primary treatment for all
forms of schistosomiasis is praziquantel, an effective antihelminthic drug. Currently, there is no
optimal treatment for Katayama syndrome (Bottieau et al. 2005), but a combinative therapy that
includes the effective antimalarial drug artemisnin, also known as artemether, coupled with
praziquantel and steroids has shown promise. However, there are some reservations that if
artemether is used for all schistosome species, including those in places like sub-Saharan Africa,
it could create selective pressures for Plasmodium spp. to become resistant to artemisnin, and
should therefore be used carefully (Bottieau et al. 2005, Ross et al. 2007). Recurrent episodes of
Katayama syndrome after treatment have become increasingly observed (Bottieau et al. 2005,
Ross et al. 2007). This recurrence might reflect shifting larvae localization or an immune
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reaction to different worm antigens from various life stages (Bottieau et al. 2005). Treatment for
the recurrence is another recommended dosage of praziquantel, 60 mg/kg for 6 days, despite the
fact that a second course will be less effective (Ross et al. 2007).
Schistosomiasis can be eliminated by behavioral changes, safe water supplies, and
sanitation, which are measures that have led to its exemplary eradication in Japan (Gryseels
2006). China’s community-based chemotherapy program that began in the 1950s has also been
one of the most successful disease control programs in history (Zhou et al. 2008), reducing the
number of human infections by over 90% in 2000 (Zhou et al. 2008). However, the effects of
climate change are causing a reemergence of schistosomiasis in China through floods. There is
also the possibility that higher temperatures will alter parasite development thresholds in a way
that increases their proliferation (Zhou et al. 2008). There are predictive risk maps created from
geographic information systems tools that show its potentially resurgent spread (Figs. 1, 2).
Ecologic transformations like the creation of dams and water development projects are
compounding this risk. The WHO estimates that greater than 150,000 deaths and 5.5 million
DALYs can be attributed to climate change and variability each year (Zhou et al. 2008). These
DALYs, as well as those attributed to schistosomiasis, might require revisions based on new
findings of the “age-specific disability weight,” as well as considerations for other associated
effects of the disease such as anemia, malnutrition, cognitive impairment, and growth retardation
(Jia et al. 2007). Age and occupation-specific factors associated with disability can confound
some of the DALY criteria as well, and these shortcomings might have led to an underestimation
of the true burden caused by schistosomiasis (Jia et al. 2007, McManus 2005).
Coupling this higher prevalence of infected individuals that have not been previously
accounted for along with the reemergence of schistosomiasis due to climate change, it becomes
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clear why the development of vaccines has become an important area of targeted research. One
proposed vaccine is attempting to address the1 million currently infected Chinese and hundreds
of thousands of livestock by inoculating reservoir hosts, specifically bovines. This “transmission
blocking vaccine” could be an effective control for schistosomiasis, especially if it is integrated
with chemotherapy. The goals of vaccines for S. japonicum are either to prevent infection or
reduce parasite fecundity. Development of such vaccines has exposed issues of impracticality
and efficacy. The promising use of irradiated cercariae is ultimately unrealistic for wide-scale
production. According to McManus (2005), feasibility of large-scale production should be the
primary selection criteria for determining vaccine candidates. Also, other available antigen
targets for protein vaccines such as the immunomodulatory paramyosin, interferon-producing
calpain, and anti-fecundity inducing 26-kDa glutathione S-transferase (GST) have an apparent
“efficacy ceiling” as candidates, as their prototype formulations induce at best only around 4050% protection in animals. Therefore, the discovery of new antigens would greatly progress the
development of a feasible and effective vaccine. These kinds of antigens, receptors, enzymes,
and genes have been identified and are currently being investigated from the wealth of
information provided by the recently sequenced genome of S. japonicum (McManus 2005).
The draft genome of the parasite has increased the knowledge base of its molecular
constituents to such a degree that scientists can make conjectural assumptions with relatively
high predictive power (Table 1). For example, comparisons of the S. japonicum to that of other
sequenced species has shown that the parasite abandoned roughly 1,000 protein domains over the
course of its evolution, alluding that this loss could partly be attributed to its adoption of a
parasitic way of life (Zhou et al. 2009). Analysis of its metabolic pathways shows a similar effect,
where the loss or degeneracy of fatty acid, sterol and purine synthesis pathways in schistosomes
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may also be due to their adoption of parasitic lifestyle. The genome has shed light on
schistosome parasite-host interactions, where it has been found that putative nervous system
receptors can accept ligands as a physiological response to freshwater or the tissues of their snail
and mammalian hosts. It is also possible that schistosomes can exploit host growth factors as
development signals in addition to their own pathways, as well as access nutritive fatty acids and
cholesterol from host blood and plasma. Genomic studies have uncovered mammalian-like
insulin, progesterone, and cytokine receptors, which could mean that schistosomes can use host
hormones to further their development (McManus 2005). Leptin, a suppressor or insulin
secretion, has been found to be encoded by the genome of S. japonicum, and further supports the
possibility that the parasite can modulate its energy metabolism in reaction to its own hormones
or those of its mammalian host (Zhou et al. 2009). Proteases such as elastase have been found to
be important for cercariae to penetrate mammalian skin. Schistosomes also appear to possess a
primitive immune system in the form of a Toll pathway, which gives them a first line of defense
against microbes. Prostaglandin synthesis and autoantigens are possessed by S. japonicum too,
leading scientists to believe that the parasites might be able to manipulate inflammatory
responses with molecular mimicry, and contribute to the granuloma formation that promotes its
survival (Zhou et al. 2009). Overall, sequencing the S. japonicum genome has single-handedly
opened a plethora of molecular avenues for finding ways to eliminate schistosomiasis (Table 1).
It has become a model for evaluating genomic architecture, biology, and evolution in this taxon
(Zhou et al. 2009) and demonstrates the power of genomic research for unveiling new
opportunities for discovery.
Future prospects for the elimination or control of S. japonicum and its associated morbid
diseases like schistosomiasis and Katayama syndrome require a thorough understanding of its
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complex life cycle and epidemiology, consideration for any reemergence due to climate or
ecological transformations, appropriate optimal treatments and preventative sanitation, education
and vaccines, and development of novel research initiatives and interventions that draw from the
parasite’s genome. The current treatment suggestions of a transmission blocking vaccine for
reservoir hosts, a dual therapy of praziquantel and artemisinin in Asia, and the use of
dimethicone barrier cream are only preliminary options in the grand scope of potential scientific
progress. The advent of the sequenced genome of S. japonicum should provide scientists with
numerous ways to elucidate current conjectures into innovative treatments and realize the
achievable elimination of schistosomiasis.
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References Cited
Bottieau, E., J. Clerinx, M. R. de Vega, E. V. den Enden, R. Colebunders, M. V. Esbroeck,
T. Vervoort, A. V. Gompel, and J.V. den Ende. 2005. Imported Katayama fever: clinical and
biological features at presentation and during treatment. J. Infection. 52:339-345.
Combes, C. 2005. The Art of Being a Parasite. University of Chicago Press. Chicago, Illinois.
Gryseels, B., K. Polman, J. Clerinx, and L. Kestens. 2006. Human schistosomiasis. Lancet.
368:1106-18.
Ingram, R. J., A. Barlett, M. B. Brown, C. Marriott, and P. J. Whitfield. 2002. Dimethicone
barrier cream prevents infection of human skin by schistosome cercariae: evidence from Franz
cell studies. J. Parasitol. 88:399-402.
Jia, T.W., X-N. Zhou, X-H. Wang, J. Utzinger, P. Steinmann, and X-H. Wu. 2007.
Assessment of the age-specific disability weight of chronic schistosomiasis japonica. B. World
Health Organ. 85: 458-465.
McManus, D. P. 2005. Prospects for development of a transmission blocking vaccine against
Schistosoma japonicum. Parasite Immunol. 27:297-308.
Ross, A. G., D. Vickers, G. R. Olds, S. M., Shah, and D. P. McManus. 2007. Katayama
syndrome. Lancet Infect. Dis. 7:218-24.
Zhou, X-N., G-J. Yang, K. Yang, X-H. Wang, Q-B. Hong, L-P. Sun, J. B. Malone, T. K.
Kristensen, N. R. Bergquist, and J. Utzinger. 2008. Potential impact of climate change on
schistosomiasis transmission in China. Am. J. Trop. Med. Hyg. 78:188-194.
Zhou, Y., H. Zheng, F. Liu, W. Hu, Z-Q. Wang, G. Lu, and S. Ren. 2009. The Schistosoma
japonicum genome reveals features of host-parasite interplay. Nature. 460:345-352.
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Fig 1. Risk map of schistosomiasis transmission in China in 2000 (A) (green color
denotes potential risk areas for schistosomiasis transmission), and (B) is a corresponding
prediction error distribution map (Zhou et al. 2008).
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Fig 2. Predicted risk map of schistosomiasis transmission in China in 2030 (A) and
2050 (B) (green color denotes potential risk areas for schistosomiasis transmission in 2000,
and blue color denotes predicted additional risk areas (Zhou et al. 2008).
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Table 1. Applicable molecules for further research toward novel interventions.
Depicts current and potential molecules that can be manipulated for the development of
vaccines or control mechanisms of S. japonicum. Compiled from combined data from
McManus (2005) and Zhou et al. (2009).
Name
Type
Paramyosin
Protein
Calpain
Cathepsin D
GST
Proteinase
Protease
Transferase
Tegumentassociated antigen
Sj23
bZIP
Oipoid, Galanin,
Melatonin receptors
Leptin, hormones
Leucine zipper
Receptor
Hypothalmic
neuropeptide
Transducins
Metabotropic
glutamate receptor 3
Transducin
Proteases
Protease
SjCE
Elastase
Toll pathway
Protein pathway
Glycans, lipids
Prostaglandins
Antigen
Prostaglandin
Autoantigens
Antigen
Receptor
Function or Application
Inhibitor, immunomodulator, Vaccine
candidate
Stimulates interferon gamma production,
synthetic vaccine candidate
Generates high levels of specific antibodies
Anti-fecundity effect, vaccine candidate
DNA vaccine candidate with significant
levels of protection
Exploitable paralogue to vertebrate specific
protein, key role in mammalian host-parasite
relationship
Ligand response to freshwater and
mammalian host environment
Energy metabolism of parasite, possible
hormone modulator
Mediate distinct responses of sensors to
signals
Sensory perception, exploitable within
parasite
Key roles in invasion, migration, and
feeding/nutrition
Enzyme vital to cercarial penetration of
mammalian skin
Line of defense against microbial infections,
primitive immune system
Enzymatic machinery for biosynthesis and
modification
Inflammatory responses
Molecular mimicry that promotes parasite
survival