Parasite Immunology, 2009, 31, 163176

DOI: 10.1111/j.1365-3024.2009.01098.x

Review Article
Immunopathogenesis
REVIEW
ARTICLEof
human schistosomiasis
Blackwell Publishing
Ltd

Immunopathogenesis of human schistosomiasis

M. L. BURKE,1,2 M. K. JONES,1,3 G. N. GOBERT,1 Y. S. LI,1 M. K. ELLIS1 & D. P. McMANUS1
1

Molecular Parasitology Laboratory, Division of Infectious Diseases and Immunology, The Queensland Institute of Medical Research,
Herston, Queensland, Australia; 2The School of Population Health, The University of Queensland, Herston, Queensland, Australia;
3
The School of Veterinary Science, The University of Queensland, St Lucia, Queensland, Australia

SUMMARY

INTRODUCTION

Schistosomiasis continues to be a significant cause of parasitic

morbidity and mortality worldwide. This review considers the
basic features of the pathology and clinical outcomes of
hepatointestinal and genitourinary schistosomiasis, presents
an overview of the numerous studies on animal models that
have clarified many of the immunopathological features, and
provides insight into our current understanding of the immunopathogenesis and genetic control of human schistosomiasis.
In murine schistosomiasis, pathology is induced by a CD4+ Th2
driven granulomatous response directed against schistosome
eggs lodged in the host liver. The Th2 cytokines IL-4 and
IL-13 drive this response, whereas IL-10, IL13R2, IFN-
and a subset of regulatory T-cells act to limit schistosome
induced pathology. A variety of cell types including hepatic
stellate cells, alternatively activated macrophages and regulatory
T-cells have also been implicated in the pathogenesis of schistosomiasis. Current knowledge suggests the immunopathogenic
mechanisms underlying human schistosomiasis are likely to be
similar. The review also considers the future development of
anti-pathology schistosome vaccines. As fibrosis is an important
feature of many other diseases such as Crohns disease and
sarcoidosis, a comprehensive understanding of the cellular and
molecular mechanisms involved in schistosomiasis may also
ultimately contribute to the development an effective disease
intervention strategy for other granulofibrotic diseases.

Schistosomiasis is a disease caused predominantly by the

hosts immune response to schistosome eggs (ova) and the
granulomatous reaction they evoke (15). The granulomas
destroy the eggs and sequester or neutralize otherwise
pathogenic egg antigens but also leads to fibrogenesis in
host tissues (4). The intensity and duration of infection, in
turn, may determine the amount of antigen released from
the eggs and the severity of chronic fibro-obstructive disease.
The majority of pathology develops at the sites of maximal
accumulation of eggs: the intestine and the liver (in the case
of Schistosoma mansoni and S. japonicum) and the genitourinary tract (in the case of S. haematobium) (1,3). However,
granulomas have been found in many different tissues,
including the skin, lung, brain, adrenal glands and skeletal
muscle (3). Extensive studies of experimental schistosomiasis,
mostly on murine S. mansoni, have revealed that granuloma
formation is attributable to a vigorous CD4+ Th2 driven
response, akin to a form of delayed-type hypersensitivity,
that is tightly regulated by various cell populations, cytokines
and chemokines (2,4,5).
This review firstly considers the basic features of the
pathology and clinical outcomes of hepatointestinal and
genitourinary schistosomiasis, and secondly provides an
overview of the extensive studies on animal models of
schistosomiasis that have clarified many of the features
governing the progression of the granulomatous reaction in
schistosome-egg induced hepatic disease. A discussion of the
current understanding of the immune-mediated pathology in
human schistosomiasis then follows. Immunopathogenic
mechanisms elucidated in mice are not easily investigated
comparatively in humans, so that knowledge of human
responses to schistosomes is far from complete. As schistosome infection in mice differs in many respects from that in
humans, caution is required in extrapolating and interpreting
results from murine experiments (46). Nevertheless, the

Keywords chemokine, cytokine, fibrosis, immunopathogenesis,

immunopathology
Correspondence: Donald McManus, Molecular Parasitology
Laboratory, Division of Infectious Diseases and Immunology,
Queensland Institute of Medical Research, PO Royal Brisbane
Hospital, Herston, QLD 4029, Australia
(e-mail: donald.mcmanus@qimr.edu.au).
Received: 27 November 2008
Accepted for publication: 9 January 2009
Disclosures: M. L. Burke, M. K. Jones, G. N. Gobert, Y.S. Li, M. K. Ellis, D P. McManus None

2009 Blackwell Publishing Ltd

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M. L. Burke et al.

basic underlying immunopathogenic mechanisms in the two

species are likely similar.

CLINICAL MANIFESTIONS OF
SCHISTOSOMIASIS
Acute schistosomiasis
Acute schistosomiasis, when it occurs, is similar during
infection with the three major schistosome species and is
characterized by cercarial dermatitis (CD) and Katayama
syndrome (KS) (3,7,8). CD is an IgE-mediated hypersensitivity
response directed against penetrating cercariae (1,3,7,8),
occurs infrequently among endemic populations but is common
among visitors and migrants and after primary infections
(1,810). CD is characterized by a maculopapular, pruritic
rash that manifests within several hours of exposure to contaminated water and may persist for several days (1,3).
KS is an immune-complex mediated hypersensitivity
reaction against migrating schistosomula and early egg
deposition (1,3,8). The symptoms of KS manifest 14 84 days
after individuals are first exposed to schistosome infection
or following heavy reinfection and are characterized by
rapid onset fever, fatigue, myalgia, malaise, headache,
nonproductive cough, and eosinophilia with patchy infiltrates
visible on pulmonary radiography (1,3,8). Abdominal symptoms may also occur and correspond with the migration of
juvenile worms (1,3,9). Acute schistosomiasis due to S. mansoni
or S. haematobium infection is common among individuals
exposed for the first time such as travellers or migrants but
is rare among endemic populations (1,3,9). In contrast,
acute disease due to S. japonicum is common in endemic
communities and is associated with severe and persistent
manifestations that may rapidly progress to hepatosplenomegaly
and portal hypertension (1,3,11).

Chronic schistosomiasis
Chronic disease in schistosomiasis is variable and is dependent
on the anatomical location of adult schistosome within the
vasculature of the mammalian host. Schistosoma japonicum
and S. mansoni infection cause hepatointestinal and
hepatosplenic disease, whereas chronic infection with S.
haematobium causes genitourinary schistosomiasis (1,3,7,8).
The outcome of chronic schistosomiasis may be further
complicated by co-infections. For example, co-infection
with S. mansoni and Hepatitis C Virus (HCV) or Hepatitis
B Virus (HBV) is associated with accelerated progression
and increased severity of chronic liver fibrosis (3,12).
Additionally, the development of ectopic lesions leading to
neuro-, cerebral or pulmonary schistosomiasis may occur
but is rare (3,13,14).

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Gastrointestinal and liver disease

Gastrointestinal schistosomiasis is characterized by chronic
or intermittent abdominal pain and discomfort, loss of
appetite and diarrhoea that commonly contains occult
blood. These symptoms are caused by a granulomatous
response to schistosome eggs in the intestinal mucosa leading
to pseudopolyposis, microulceration and superficial bleeding
(3,9,10). Hepatosplenic schistosomiasis begins with the
deposition of schistosome eggs in the hepatic sinusoids
leading to the development of granulomas and hepatomegaly.
Chronic infection and granulomatous inflammation leads to
the excess deposition of collagen and other extracellular
matrix (ECM) components in the liver causing periportal
fibrosis and progressive occlusion of the portal veins. In
turn, occlusion of the portal veins leads to the development
of portal hypertension, splenomegaly, portacaval shunting,
ascites, gastrointestinal varices and gastrointestinal bleeding
that may eventually be fatal (1,3,13,14). Blood loss through
haematuria (S. haematobium), intestinal and variceal bleeding,
malnutrition and the production of haemolytic factors by
schistosomes can lead to anaemia in schistosomiasis (15).
Anaemia, in turn has been associated with wasting in
adults and growth retardation and cognitive impairment in
children (1,3). In S. mansoni infection progression to
chronic hepatosplenic schistosomiasis takes 515 years
while for schistosomiasis japonica progression to chronic
disease is more rapid and severe with little or no interval
between acute and chronic disease (1).
Genitourinary disease
Genitourinary tract disease is a specific trait of S. haematobium
infection (1,3,16). Adult S. haematobium worms inhabit the
vasculature surrounding the genitourinary tract leading to
the deposition of schistosome eggs in the wall of the bladder and
the ureters. Chronic infection induces fibrosis and calcification
of the bladder and ureters and is often complicated by secondary
bacterial super-infections. Chronic disease typically manifests
as renal colic, hydroureter and hydronephrosis that in severe
cases, may culminate in renal failure (1,3,17).
One-third of women infected with S. haematobium will
also develop genital schistosomiasis (17). Granulomas
around eggs lodged in the vulva, vagina or cervix produce
ulcerative lesions that are an increased risk factor for the
transmission of sexually transmitted infections such as HIV
(1,17). Involvement of the uterus, fallopian tubes and
ovaries is less common but fibrotic scarring induced by the
granulomatous response may lead to infertility. Genital
schistosomiasis is less frequent in males and is characterized
by haematospermia and may affect the epididymis, testicles and
the spermatic chord (1,17). Genitourinary schistosomiasis
has also been epidemiologically linked to carcinoma of the
bladder in Egypt and other African foci (1,3,17).
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Diagnosis and treatment of schistosomiasis

Diagnosis of both acute and chronic schistosomiasis is
currently dependent on the detection of antibodies against
parasite antigens or schistosome eggs in the faeces or urine
(3,8). Acute schistosomiasis is further characterized by the
presence of diffuse pulmonary infiltrates on chest X-ray and
almost all cases present with eosinophilia and a history of
water contact (1,3,8). These patients respond well to treatment with praziquantel (PZQ) with and without steroids
(3). Artemether (ART) treatment given early after exposure
may decrease the risk of KS (3,8). Combination therapy
with PZQ and ART has been shown safe but is no more
effective than PZQ alone against acute schistosomiasis
japonica (18).
Ultrasonography provides a safe, rapid, and noninvasive
method for the assessment of pathology associated with
chronic hepatosplenic disease (1922). Based on WHO
guidelines, the image pattern of liver texture and objective
measurements of wall thickness of a peripheral segmental
portal vein and main portal vein diameter are used to grade
the degree of hepatic fibrosis (23). The grade of fibrosis is in
turn used as a predictive factor for the development of
portal hypertension and gastrointestinal bleeding (2022).
Ultrasonography may also be used to assess the effectiveness
of anti-schistosomal therapy in advanced disease (24).
Magnetic resonance imaging (MRI) has shown high sensitivity
and specificity for differentiating between cirrhosis and
chronic hepatosplenic schistosomiasis (25). Biochemical
markers of liver fibrosis (pro-collagen peptides type III and
IV, the P1 fragment of laminin, hyaluronic acid, fibrosin,
TNF-R-II and sICAM-1) have the potential to provide a
highly sensitive and cost effective method for the assessment
of schistosome induced fibrosis but are still under investigation (1,24,26). IL-13 production by PBMCs may be a
useful indicator of the persistence of fibrosis following
treatment (27).

IMMUNOPATHOLOGY OF HEPATIC
SCHISTOSOMIASIS

Immunopathogenesis of human schistosomiasis

of the exudative stage. As the granuloma matures into the

exudative-productive stage, histiocytes and epitheloid cells
begin to appear at the periphery and gradually replace the
leukocytic zone. Fibrocytes also appear at the periphery of
the lesion and form an outer zone around the histiocytes
and epitheloid cells.
During the productive stage, the schistosome egg
becomes degenerated and disintegrated, fibrocytes and
collagen fibres become more prominent and lymphocytes,
histiocytes, plasma cells and some eosinophils form an
additional zone at the periphery of the lesion. Fibrocytes
and collagen fibres eventually become the predominant
feature of the granuloma whereas other cell types diminish
in number (28,30). Granulomas of the involutional stage are
greatly reduced in size and may exhibit hyalization of collagen
fibres, whereas the egg is typically disintegrated and may
become calcified (28,30).
An effective T-cell response is known to be critical for the
development of the granulomatous response and host survival.
Nude mice infected with a Chinese strain of S. japonicum
supported normal parasite survival and fecundity, although
transitory growth retardation occurred during the early
stage of infection (32). Also, these T-cell deprived mice
develop severe necrosis around the eggs in the liver, a situation
akin to T-cell-deprived mice infected with S. mansoni but
not to that observed in nude mice infected with Philippine
S. japonicum (33). These discrepant pathological events in
the nude mouse may represent an example of the recognized
differences in biological characteristics between S. japonicum
strains (32).
B-cell function is required for S. japonicum egg-induced
granuloma pathology in early infection (34). OBF-1 knockout
mice and MT mice, both with impaired B-cell development,
developed significantly smaller hepatic granulomas at 5 weeks
post-infection compared to their wild-type counterparts. In
contrast, they displayed no significant difference in granuloma
pathology at eight weeks post-infection. This is in concordance
with some studies on S. mansoni, also using B-cell-deficient
mouse models, which have suggested that B-cells are required
for Th2 T-cell responses but not for granuloma formation
late in infection (34,35).

Cellular kinetics of the granuloma

Early studies in mice, rhesus monkeys (28) and, later, in pigs
(2931) demonstrated that the granulomatous response
around schistosome eggs develops through five pathological
stages: the weakly reactive, exudative, exudative-productive,
productive and involutional stages (28,30).
The weakly reactive stage is characterized by a gradual
accumulation of mononuclear cells, neutrophils and
eosinophils around the freshly deposited egg that leads to
the formation of a neutrophilic microabscess characteristic
2009 Blackwell Publishing Ltd, Parasite Immunology, 31, 163176

Cellular kinetics of hepatic fibrosis

Bartley et al. (36) demonstrated that, in the liver of mice
infected with Philippine S. japonicum, activated hepatic
stellate cells (HSCs; SMA+, GFAP+, Desmin+) localize
to the periphery of hepatic granulomas, adjacent to fibrotic
areas. Similarly, Chang et al. (37) observed a predominance
of SMA+, GFAP+ activated HSCs in the liver during
human schistosomiasis mansoni. Together these findings led
to the hypothesis that HSCs are the main ECM producing

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cells in schistosome-induced hepatic fibrosis. In response to

tissue damage, these cells undergo transdifferentiation
into activated myofibroblast-like cells that produce ECM
components, as well as fibrogenic cytokines, Matrix
Metalloproteinases (MMPs) and Tissue Inhibitors of
Metalloproteinases (TIMPs) that contribute to the remodelling
of fibrotic tissue in murine and human schistosomiasis
(36,38). Related studies have shown that cumulative fibrosis
of the liver (39) and colon (40) of mice infected with S. mansoni
is associated with an imbalance in MMP:TIMP expression
and elevated levels of fibrogenic cytokines. Control of HSC
activation and activity may therefore prove important in
regulating pathology because of schistosomiasis. Prostaglandin
E1 (PGE1) effectively protects rabbit liver from fibrosis, at
least in part by inhibiting the activation of HSCs, raising the
possibility of combining praziquantel and PGE1 treatment
to reverse hepatic fibrosis caused by schistosomiasis (38). There
is evidence, however, that non-HSC derived liver myofibroblasts
may also be involved in this complex process (41,42).
Alternatively activated macrophages (aaM) are
hypothesized to contribute to schistosome induced fibrosis
(4,5,43,44). Alternative activation of macrophages is induced
by Th2 responses and promotes collagen synthesis and
fibrogenesis via the metabolism of l-arginine to proline and
polyamine by Arginase-1 (Arg-1 4,43,45,46). Cationic amino
acid transporter-2 (CAT-2) may be an important regulator
of this process by modulating the activity of Arg-1 (47). Furthermore, Fizz-1 (Found in inflammatory zone-1/RELM ),
a surface molecule of aaM , may induce activation of
fibroblasts (4,48).
Despite the similarities in S. mansoni and S. japonicum
granuloma formation demonstrated by different animal
models, some important differences exist between granulomas
elicited by these parasites. Schistosoma japonicum eggs tend
to be laid in clusters favouring the development of large
lesions that are more neutrophilic (28,49). As well, the much
higher egg production by S. japonicum (10 times that of S.
mansoni) results in increased pathology (3). The smaller size
of S. japonicum eggs allows them to be swept to the small
portal veins and causing fibrosis in both the peripheral and
central areas of the liver (50,51), whereas S. mansoni eggs
remain in the large portal veins and cause fibrosis in the
central part of the organ (50,51). Calcification of S. japonicum
eggs is common but occurs rarely for S. mansoni eggs (28,52).
Nevertheless, extensive studies by Cheever et al. (e.g. Ref (33))
suggest the immunopathogenic mechanisms associated with
these two forms of schistosomiasis are likely to be similar.

Kinetics of the Th1/Th2 response to schistosome infection

The major components of the schistosome induced granulomas
and the cytokines and chemokines that drive this response

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are illustrated in Figure 1. During the first 46 weeks of

infection in the mouse, a moderate T-helper type 1 (Th1)
response is generated against migrating schistosomula and
immature adult worms. This response is characterized by
increased levels of circulating pro-inflammatory cytokines
including TNF-, IL-1, IL-6 and IFN- (2,4,5,36,53).
Elevated levels of these cytokines have also been associated
with the development of KS in humans (16). The immune
response then switches to a T-helper type 2 (Th2) dominant
response with the onset of egg-laying, characterized by
increased expression of IL-4, IL-5, IL-10 and IL-13
(2,36,53,54). The Th2 response reaches a peak at approximately 8 weeks post-infection and is then down-modulated
with progression to chronic infection (2,4,5,54).

Cytokine regulation of the granulomas and fibrosis

Pivotal studies with IL-13 and IL-4 deficient and IL-13/
IL-4 doubly deficient mice demonstrated that IL-4 drives
the development of the granulomatous response whereas
IL-13 is the key profibrotic cytokine in the development of
schistosome induced hepatic fibrosis (55). IL-4 is responsible
for determining granuloma size, inducing the proliferation
of Th2 cytokine-producing lymphocytes and is important
for the production of IL-5 and IL-13 by granuloma associated
cells (5660). Furthermore, IL-4 is not required for the
development of fibrosis but enhances the effects of IL-13 on
fibrogenesis (55). As well as promoting fibrosis, IL-13 is
known to have an additive effect with IL-4 in the establishment
of the Th2 dominant, eosinophil-rich, granulomatous reaction
(55). Kaviratne et al. (61), by using mice deficient for TGF-,
demonstrated that IL-13 acts directly on target cells to activate
fibrogenic pathways in a TGF- independent fashion.
Furthermore, the key role of IL-13 and IL-4 in fibrogenesis
is evidenced by their effects on the proliferation of and
production of collagen by LI90 cells, a human HSC line
(62). LI90 cells express the type-II IL-4 receptor complex
(IL-4R/IL-13R1) for IL-4 and IL-13 and up-regulate collagen
production in response to treatment with recombinant IL-4
or IL-13. The type-II IL-4 receptor signalling is important
in the development of fibrosis, chronic morbidity and mortality
not only in schistosomiasis, but also in allergic asthma (63).
Additionally, IL4-R expression on nonbone marrow
derived cells is required for granuloma formation and
fibrosis during S. mansoni infection (64). IL-4 and IL-13
may also contribute to the development of fibrosis by inducing
the alternative activation of macrophages (4,43,45,46).
IL-5 is required for the recruitment of eosinophils to the
granulomatous response as granulomas in mice deficient in
IL-5 are virtually devoid of these cells (65). Eosinophils are
an important source of Th2 cytokines such as IL-13 (59)
and, therefore, IL-5 indirectly contributes to the polarization
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Immunopathogenesis of human schistosomiasis

Figure 1 Major components of the granulomatous response to schistosome eggs in the host liver and the main cytokines and chemokines
that regulate this response. Legend: Egg, Neutrophil, Eosinophil, Macrophage, Hepatic Stellate CellFibroblast, Collagen Fibres, CD4 +
T-cell/B-cells, Hepatocytes.

of the immune response through the recruitment of these

cells (59,66). It has been proposed that IL-2 regulates the
expression of IL-5 as production of IL-5 is significantly
reduced in schistosome infected mice with treated with an
anti-IL-2 mAb (67,68). The recruitment of the large numbers
of eosinophils to granulomas in both humans and mice
suggest these cells contribute to the disease process although
their precise role remains undetermined (69,70).
IL-10 plays a key regulatory role in facilitating the shift
from a Th1 to Th2 response and preventing the development
of severe pathology due to excessive Th1 and/or Th2
responses (4). In the early stages of the granulomatous
response, IL-10 acts to suppress the production of Th1
cytokines such as IFN- (71,72), possibly by regulating
IL-12/IL-12R expression which, in turn, modulates IFN-
expression (73). Hoffmann et al. (74) have also demonstrated
that IL-10 is essential to prevent excessive Th2 responses in
IL-10 knockout mice.
2009 Blackwell Publishing Ltd, Parasite Immunology, 31, 163176

The role of Th1 cytokines in schistosome induced

granulomas and fibrosis are not as well defined. Experiments with IFN- knockout mice (58) and anti-IFN- mAb
(65) treated mice have shown that in schistosomiasis japonicum,
IFN- is critical in the development of granulomas and
contributes to the recruitment of neutrophils to the
granulomatous response. Results with IFN- deficient mice
infected with S. mansoni have been conflicting with reports
of reduced, increased or no change in granuloma sizes compared with wild-type controls (57,58).
The recent description of a third T-helper-cell subset
(Th17) and its involvement in a variety of other chronic
inflammatory diseases has prompted investigations of its
role in schistosomiasis (75). The Th17 subset does not
appear to be involved in the pathogenesis of schistosomiasis
in mice with moderate pathology but has been associated
with the development of severe pathology in Th1 polarized
mice and CBA mice that develop a strong inflammatory

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Table 1 Comparison of the pathology and cytokine responses in schistosomiasis mansoni and schistosomiasis japonica
Schistosomiasis mansoni

Schistosomiasis japonica

Egg laying commences 6 weeks post infection

Eggs are laid singly (28)

Egg laying commences 3 4 weeks post infection

Eggs are laid in clusters leading to the formation of larger
granulomas (28)
Granulomas are composed predominantly of neutrophils (28)
Calcification of eggs within granulomas is common (28)
The response of infected mice to purified SEA is of an
immediate-type-hypersensitivity reaction (79)
Katayama Syndrome is common in endemic regions and its
symptoms are more severe (1)
Fibrosis occurs in the centre and the periphery of the liver (50,51)
IL-4/ knockout mice have an impaired granulomatous response (58)

Granulomas are composed predominately of eosinophils (28)

Calcification of eggs within granulomas is infrequent (28)
The response of infected mice to purified SEA is of a
delayed-type-hypersensitivity reaction (79)
Katayama Syndrome occurs mainly in previously unexposed
individuals and is uncommon in endemic regions (1)
Fibrosis occurs in the central region of the liver (50,51)
IL4/ knockout mice have granulomas of a similar size to
wild-type mice (55)
Anti-IL-5 antibody treatment does not affect the size of
granulomas (80)
Anti-IFN- antibody treatment increases granuloma size (57)
while IFN- deficiency has no effect (81)

response characterized by high levels of IFN- (4,7678).

The induction of severe pathology and expression of IL-17
in Th1 polarized mice has subsequently been shown to be
dependent on the presence of IL-23, another Th17 cytokine
(76,77).
Although the immunopathology of S. mansoni and
S. japonicum infections appears to be similar, there are
indications that S. mansoni and S. japonicum-induced pathology
responds differently to cytokine regulation, at least in the
mouse, and these differences in cytokine response might
provide important clues regarding the progression to chronic
disease (58). A comparison of the pathology and cytokine
responses in schistosomiasis mansoni and schistosomiasis
japonica is shown in Table 1.

Regulation of the granulofibrotic response

Tight regulation of the Th1, Th2 and possibly Th17 cytokine
responses generated during schistosome infection is
essential to prevent excessive pathology. As discussed above
IL-10 plays key roles in facilitating the switch from a Th1 to
a Th2 dominant response with the onset of egg laying and
in preventing the development of an excessive Th2 response
which would be detrimental to host survival.
Binding of parasite antigens by pattern recognition
receptors on dendritic cells (DCs), macrophages and other
immune cells may play a role in the polarization of the
immune response against schistosome eggs. For example
Galectin-3, a cell surface molecule that binds glycoconjugates,
is important in host defence against other pathogens but
reports of its role in the development of Th2 responses and
overall egg granuloma formation are contradictory (8284),
so its relevance in murine schistosomiasis remains elusive.

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Anti-IL-5 antibody treatment decreases granuloma volume (65)

Anti-IFN- antibody treatment and IFN- deficiency decreases
granuloma size (58,65)

Regulatory T-cells (Tregs) also help regulate the

granulofibrotic response. These cells are classified as a
CD4+CD25+ subset of T-cells that may be divided into
naturally occurring Tregs (naTregs) or inducible Tregs
(iTregs). Naturally occurring Tregs are characterized by the
expression of forkhead/winged helix transcription factor 3
(FoxP3) and are recruited to the site of inflammation after
undergoing selection in the thymus. Inducible Tregs are
FoxP3 and develop in the periphery from activated effector
cells (4,85). Studies using an adoptive transfer model in IL10/Recombination activating gene-2(RAG-2)-deficient mice
have demonstrated that iTregs are an important source of
IL-10 that regulates Th1/Th2 balance during schistosomeinduced pathology (71). In a follow up study naTregs were
shown to be capable of suppressing the expression of both
Th1 and Th2 cytokines (86). T-regulatory cells therefore
contribute to the regulation of schistosome-induced pathology
by both suppressing the Th1 response and preventing the
development of an excessive Th2 response during the
development of granulomatous inflammation (4,71,85,86).
The regulation of T-cells and Th2 response in schistosome
infection is however complex (87) and the precise contribution
of CD4+CD25+ T-cells to the overall regulatory process of
granuloma formation is uncertain. Most work on CD4+CD25+
cells has been undertaken on S. mansoni infection but
there is evidence they are also activated by S. japonicum
eggs (88) and may play a role in protection in against murine
models of ulcerative colitis (89) and asthma (88).

Down Modulation of the Th2 driven granulomatous response

Down-modulation of the granulomatous response is essential
to prevent excessive chronic morbidity and to promote host
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survival (90), and is characterized by a decreased cellular

inflammatory response to newly deposited eggs and the
simultaneous down regulation of the Th2 cytokine
responses (2,44). Multiple mechanisms are thought to be
involved in this down modulation. Elegant studies in murine
schistosomiasis have revealed that IL-13R2 is essential for
the down-regulation of the granulomatous response and is
pivotal in the control of IL-13-mediated fibrosis (4,9092).
IL-13R2 acts as a potent decoy receptor, competing with
IL-13R1 for binding of IL-13 and preventing signalling
through the IL-4/IL-13R1 receptor complex (4,9092).
The dynamics of IL-13R1 and IL-13R2 expression
may therefore influence the outcome of schistosomiasis and
defining how their expression it regulated is an important
area for future investigation, not only for understanding
granuloma modulation in schistosomiasis but also for other
Th2-associated diseases (4). A role for apoptosis, particularly
apoptosis by neglect of CD4+ T-cells, has been hypothesized
to contribute to the down-modulation of the granulomatous
response (93). Apoptosis of CD4+ T-cells has been shown to
occur at a higher rate in low pathology C57BL/6 mice which
develop smaller granulomas compared with high pathology
CBA mice (93). B-cell mediated FcR dependent signalling
has also been implicated in the down-modulation of the Th2
response as mice deficient in B-lymphocytes or the Fcreceptor exhibited marked exacerbation of granulomatous
inflammation (35).

Chemokines in hepatic schistosomiasis

The activities chemokines in schistosome-induced hepatic
fibrosis are poorly understood, but one likely role lies in
cellular recruitment of cells to the granuloma (44,94). CCL3
(Macrophage Inflammatory Protein-1; MIP-1), CCL17
(Thymus and Activation Regulated Chemokine; TARC)
and CCL22 (Macrophage Derived Chemokine; MDC) are
thought to promote the granulofibrotic response as mice
deficient in these chemokines develop smaller granulomas
and less fibrosis (9496). Furthermore, human studies
report an association between elevated plasma CCL3 and
an increased risk of developing severe hepatic disease,
suggesting that CCL3 may be a determining factor in the
development of severe schistosomiasis (94,97). In contrast,
CCL5 (Regulated on Activation Normal T-cell Expressed
and Secreted; RANTES) is thought to negatively regulate
granuloma development as mice deficient in this chemokine
show significant augmentation of the granulomatous
response (98). Expression of genes encoding other chemokines
and chemokine receptors such as CCL2 (Monocyte
Chemoattractant Protein-1; MCP-1), CCL4 (MIP-1),
CCL7 (MCP-3), CCL11 (Eotaxin-1), CCL12 (MCP-5),
CCR1, CCR2, CCR3 and CCR4 have been shown to be
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Immunopathogenesis of human schistosomiasis

induced in pulmonary models of schistosome induced

granuloma formation (99102) but the effect of these
chemokines on granuloma formation and fibrosis is unknown.
Together these findings suggest the balance of chemokine production and chemokine receptor activation is likely
important in determining the fate of schistosome infection
in animals and humans (103).

A MOLECULAR PROFILE OF
SCHISTOSOMIASIS
Despite the numerous studies in mice documenting the
effects of immune polarization or specific cytokines on
schistosome induced granuloma formation and fibrosis,
little is known of the global molecular mechanisms involved
or the gene signalling pathways involved in granuloma
formation and ECM remodelling (5). Results from a series
of tissue microarray studies of murine schistosomiasis
(104,105) have, however, shed some light on the molecular
and biochemical mechanisms regulating S. mansoni-induced
pathology and have confirmed the important role of Th2
cytokines in granuloma formation and fibrogenesis. The
studies used microarray analysis of mRNA extracted from
granulomatous tissues from type-1 (Th1) polarized (IL-10/
IL-4 knockout mice; limited granulomatous pathology),
type-2 (Th2) polarized (IL-10/IL-12 knockout mice; pronounced granulomatous pathology) and wild-type mice,
either infected with S. mansoni or sensitized intraperitoneally
and challenged intravenously with S. mansoni eggs, to define
the global gene expression profiles that characterize the
distinct pathological and immunological mechanisms
affecting the outcome of infection.
Type-1 polarization leads to the development of smaller
nonfibrotic granulomas but is associated with increased
tissue damage because of the development of a strong
pro-inflammatory response (74). Accordingly, genes upregulated in these mice were associated with IFN- activation
including chemokines and chemokine receptors associated
with a type-1 response such as CCL5 (RANTES) and CXCL10
(IFN--inducible protein-10; IP-10) (105). Increased tissue
damage observed in these mice was reflected in the identification of two additional major groups of genes associated
with the immune response in type-1-polarized mice: those
involved in the acute-phase reaction and those in apoptosis
(104). The up-regulation of macrophage C-type lectin and
the absence of arginase expression suggest the predominance
of classically activated macrophages, presumably contributing
to the pro-inflammatory response via the production inducible
nitric oxide (NO) (105).
Type-2 polarization induces the development of large,
eosinophil rich granulomas and excessive fibrosis (74). The
gene expression profile of these mice was associated with

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Parasite Immunology

Table 2 Differences between the murine model of schistosomiasis and human disease (After Abath et al. (6))
Murine model

Human disease

Experimental infections involve a single exposure

Intensity of infection is generally high
Animals are infected with defined schistosome isolates
Duration of infection and parasite burden are defined

Most infections are acquired gradually and involve continued re-exposure

Infection intensity varies but is generally low
Infection occurs with various isolates of the parasite
It is difficult to define how long individuals have been infected and the
parasite burden
Studies with similar parasite burden are difficult to control and
re-infection is a complicating factor
Chronic liver disease is characterized by Symmers pipe stem
(periportal) fibrosis

Studies are conducted in animals with similar

parasite burden
Some pathological features of chronic infection are
difficult to reproduce in mice, e.g. experimental
infections exhibit perioval fibrosis
Genetic background of the host can be homogeneous
Experimental design defines the length of investigation
Co-infection with other parasites can be avoided

Genetic background of the host is heterogeneous

Long-term investigation of patients with active disease is ethically precluded
Co-infection with other parasites is common and may influence the
outcome of infection

wound healing and fibrogenesis and was characterized by

the massive up regulation of procollagens, enzymes involved
in collagen synthesis and tissue repair and enhanced expression of IL-13 (104,105). A number of genes, including those
coding for small proline-rich proteins (SPRRs) (105),
associated with wound healing were increased (akin to the
response that is critical for rapid cure in murine cutaneous
leishmaniasis (106)); and there was high expression of
Arg-1, Ym1, and FIZZ-1 (105) most likely reflecting the
continuing presence and activity of a large population of
aaM in granulomatous tissues, consistent with the proposed
role of these cells in schistosome induced fibrosis. A variety
of chemokines including CCL8 (MCP-2), CCL7 (MCP-3),
and CCL12 (MCP-5), as well as CCL17 (TARC), CCL6
(C10), CCL11 (Eotaxin), and CCL24 (Eotaxin-2) were
preferentially expressed in the type-2 mice (105), likely
recruiting activated Th2 cells, eosinophils, and monocytes;
several markers of eosinophil activation such as eosinophilassociated ribonucleases were also up-regulated. Overall,
these results clearly illustrated that the different pathological
outcomes of Type-1 and type-2 polarization in the murine
model of schistosomiasis are associated with distinct gene
expression profiles. Type-1 responses promote a more
pro-inflammatory outcome leading to increased apoptosis,
whereas type-2 responses promote gene transcription
pathways associated with granuloma formation, collagen
synthesis and matrix remodelling.
Gene expression profiling of splenic CD4+ T-cells confirmed
that progression of S. japonicum infection is associated with
a switch from a Th1 to Th2 dominant response that involves
the up-regulation of a variety of immune regulators, including
many cytokine and chemokine genes, immunoglobulinrelated genes, and genes related to apoptosis and the stress
response (107,108). The onset of egg laying was associated
with an increase in the ratio of IL4+CD4+ T-cells: IFN-

170

+CD4+ T-cells and was reflected by increased expression

of the Th2 cytokines IL4 and IL-10 (107,108). Conversely, a
significant portion of the genes that were down-regulated
encoded IFN--inducible molecules suggesting that, although
IFN- expression was up-regulated, IFN signalling and the
Th1 response may be impaired during S. japonicum infection
(108). The observed switch to a Th2 dominant response was
associated with increased apoptosis of CD4+ T-cells and an
increase in the number CD4+CD25+ regulatory T-cells, consistent with the proposed roles of apoptosis and regulatory
T-cells in regulating the immunopathogenesis of schistosomiasis (71,86,93,107).

IMMUNOPATHOLOGY IN HUMAN
SCHISTOSOMIASIS
It remains to be determined to what extent the pathological
pathways established for the murine model of schistosomiasis
can be directly extrapolated to humans particularly in light
of the important differences existing between schistosomeinduced disease in the two hosts (Table 2) (6,109). For
example, some features of chronic human schistosomiasis
such as a low and sustained intensity of infection and the
pattern of Symmers pipestem fibrosis are difficult to
replicate in mice (6). Indeed, in humans, the regulation of
liver fibrosis during schistosomiasis may be even more
complex with multiple mediators, including re-infection,
co-infections, environmental factors and the age, gender and
genetic background of the host, influencing the outcome of
infection (6,110).
Studies in human patients of the association between
disease severity and the production of cytokines and/or
chemokines in vitro have shown that different clinical forms
of schistosomiasis are associated with distinct immunological
profiles (111,112). Patients with intestinal schistosomiasis
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Volume 31, Number 4, April 2009

(INT) typically display a mixed Th1/Th2 response with

higher levels of IL-4 production in comparison to acute
schistosomiasis (111). INT patients also have an increased
frequency of IL-10+ T-cells as well as CD4+CD25High+ Tcells in the peripheral blood (112). Following in vitro antigen
stimulation, PBMCs from patients with INT showed higher
expression of CXCR4+, and low expression of CXCR3+
where CXCR4 expression was closely associated with IL-10
expression (112). Patients with hepatic fibrosis (HF) exhibit
an increased number of IL4+ and IL5+ T-cell subsets compared
with patients with hepatosplenic disease, but fewer IL10+
T-cells in comparison to patients with intestinal disease
(112). Furthermore, low levels of IFN- production against
soluble egg antigen (SEA) (113115), elevated levels of
TNF- against SEA (113), high levels of IL-4 against
soluble worm antigen preparation (SWAP) and elevated
levels of IL-10 against both SWAP and SEA (114) have been
associated with an increased risk of developing severe HF.
Additionally, high levels of the Th2 cytokines IL-4 against
SWAP and IL-13 and IL-5 against SWAP and SEA correlate
with the persistence of fibrosis following treatment with
praziquantel (114). Up-regulation of activation-related
surface markers on eosinophils from chronic S. mansoniinfected patients as well as increased levels of eosinophils
derived cytokines, including TNF-, IL-4 and IL-5, in the
blood have been shown to be a hallmark of periportal
fibrosis (116). In addition, a lack of association between
cytokine production, activation marker expression, and the
number of IL-10 positive lymphocytes in the fibrotic group
suggest that impaired IL-10-driven immunoregulatory
function may play an important role in the establishment of
pathology in patients with periportal fibrosis (116). In
contrast, patients with hepatosplenic disease (HS) have
an impaired Type-2-immune response associated with
increased production of IFN- following stimulation with
SEA or SWAP (111) and decreased expression of IL-10 by
T-cells (112) that leads to the development of a predominant
pro-inflammatory immune response. Taken together the
results of these studies suggest that the outcome of human
schistosomiasis is influenced by the nature of the Th1/Th2
immune response against schistosome antigens and is regulated by IL-10 and a putative population of CD4+CD25High+
regulatory T-cells.
Overall, the results of these studies tend to corroborate
those in mice suggesting that Th2 cytokines, including IL-4
and IL-13, promote immunopathology while IFN- protects
against the development of severe fibrosis (4). The situation
may be more complex in schistosomiasis japonica where
IFN- is associated with protection against peripheral
portal fibrosis, but IL-10 is associated with protection against
central portal fibrosis, because of its anti-inflammatory and
anti-fibrotic effects (117). The pro-inflammatory cytokines
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Immunopathogenesis of human schistosomiasis

IL-1 and IL-6 are elevated in sera of S. japonicum-infected

individuals with severe hepatic fibrosis (118).

GENETIC CONTROL OF ADVANCED

SCHISTOSOMIASIS
Genetic background plays a pivotal role in determining the
susceptibility to and outcome of schistosome infections
(119124). Segregation analysis of a Brazilian population
has revealed that susceptibility to infection is controlled by
the SM1 (S. mansoni 1) gene locus that has been linked to
the 5q31q33 chromosome region comprising the genes IL4,
IL5 and IL13 (125,126), although other polymorphisms in
genes of the type-2 cytokine pathway may also be important
(127). Further, two single nucleotide polymorphisms within
IL-5 have been associated with the development of symptomatic
infection with S. japonicum in a Chinese population (124).
Another study involving a Sudanese population indicated
that the segregation of a co-dominant gene (SM2) could
account for the familial distribution of severe schistosomiasis
mansoni in this population. Linkage analysis indicated
that this gene occurred within the 6q22q23 region with
polymorphisms close to and in the IFN- receptor 1 gene
(IFNGR1)(122). A later study of an Egyptian population
confirmed linkage of severe schistosomiasis with the
IFNGR1 locus and also suggested a possible association
with the IL-13/IL-4 region and the TGF- 1 gene (119).
Further, IFN- production by egg-antigen stimulated PBMCs
correlates with protection against severe schistosomiasis
mansoni (115) and two polymorphisms in IFN- have been
found to be associated with advanced hepatic disease (121)
consistent with the anti-fibrogenic role of IFN- and the low
IFN- production by subjects with severe disease (121,128).
As indicated previously, IFN- is also associated with protection against peripheral fibrosis in humans infected with
S. japonicum whereas IL-10 protects against severe hepatic
central fibrosis and it is likely the two fibrotic outcomes are
under different genetic control (117).
Associations have also been reported between the clinical
manifestations of chronic schistosomiasis mansoni and
japonica and gene alleles within the major histocompatibility
complex (120,129134) although no consistent picture has
emerged from these studies.

CONCLUDING COMMENTS
Despite extensive studies, there is still much that remains
unknown about the immunopathology of schistosomiasis
not only that caused by S. mansoni but also by S. japonicum
and, especially, S. haematobium. As well, further work is
required to gain a better understanding of immune processes
regulating development of pathology in the human liver and

171

M. L. Burke et al.

to confirm assumed similarities to murine models of the

disease. A more comprehensive understanding the immunopathological mechanisms and gene-expression pathways
that underlie the development of chronic schistosomiasis will
be essential if new therapeutic strategies such as pathology/
morbidity limiting anti-schistosome vaccines are to be developed.
Schistosomiasis continues to be an important cause of
parasitic morbidity and mortality globally and recent
systematic reviews (135138) indicate that the geographical
extent and burden of the disease exceed official estimates.
Collectively, close to 800 million individuals are at risk of
schistosomiasis, and over 200 million people are infected in
many parts of South America, the Middle East, and
Southeast Asia, but being particularly pronounced in
sub-Saharan Africa (136). The continued spread of the
disease and reports of praziquantel treatment failures have
highlighted the need for the development of drug alternatives and new control strategies against schistosomiasis
including the use of vaccines (139,140).
Protection against schistosomiasis should not only reduce
infection and protect from re-infection, but also enhance
immune responses in infected humans that offer protection
against granuloma-related pathology and/or worm fecundity
(140), which is a characteristic of one anti-schistosome
vaccine candidate, Sh28GST, that has progressed the furthest
toward clinical development (at the Phase II Clinical Trial)
(141). Anti-pathology schistosome vaccines could be designed
to prevent the development of fibrosis and chronic morbidity
by skewing the immune response (142144). This could be
achieved by priming the immune system towards a Th1
phenotype by immunization with SEA, principal egg components recently identified by proteomic analysis (145,146),
or with appropriate recombinant antigens or DNA plasmids
(140), suitably adjuvanted with, for example, IL-12. Care
will need to be taken with this approach since murine
studies have shown that immune responses skewed in the
Th1 direction may also lead to exacerbated pathology and
premature death (74,147).
Finally, fibrosis is important to many other diseases such
as Crohns disease and sarcoidosis, and is also a major complication in asthma, chronic graft rejection, and several
autoimmune diseases (148,149). The understanding of the
cellular and molecular mechanisms involved in fibrogenesis
and the immunopathogenesis caused by schistosomes may have
broad implications for human health, ultimately translating
into an effective disease intervention strategy not only for
schistosomiasis but also for other granulofibrotic diseases.

ACKNOWLEDGEMENTS
The authors research on schistosomiasis is supported by
the National Health and Medical Research Council of

172

Parasite Immunology

Australia, The Wellcome Trust (UK) and the Dana Foundation (USA). The first author is a recipient of a University of
Queensland Joint Research Scholarship.

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