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International Journal for Parasitology 43 (2013) 301–310
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International Journal for Parasitology
journal homepage: www.elsevier.com/locate/ijpara
Invited Review
Immunomodulation by helminth parasites: Defining mechanisms and mediators
Henry J. McSorley ⇑, James P. Hewitson, Rick M. Maizels
Institute of Immunology and Infection Research, University of Edinburgh, UK
a r t i c l e
i n f o
Article history:
Received 16 October 2012
Received in revised form 28 November 2012
Accepted 29 November 2012
Available online 3 January 2013
Keywords:
Excretory-secretory products
Hygiene hypothesis
Immunomodulators
a b s t r a c t
Epidemiological and interventional human studies, as well as experiments in animal models, strongly
indicate that helminth parasitic infections can confer protection from immune dysregulatory diseases
such as allergy, autoimmunity and colitis. Here, we review the immunological pathways that helminths
exploit to downregulate immune responses, both against bystander specificities such as allergens and
against antigens from the parasites themselves. In particular, we focus on a highly informative laboratory
system, the mouse intestinal nematode, Heligmosomoides polygyrus, as a tractable model of host-parasite
interaction at the cellular and molecular levels. Analysis of the molecules released in vitro (as excretorysecretory products) and their cellular targets is identifying individual parasite molecules and gene
families implicated in immunomodulation, and which hold potential for future human therapy of
immunopathological conditions.
Ó 2013 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.
1. Introduction
The increasing tempo of reported beneficial effects of helminth
infections in the prevention or suppression of immune dysregulatory diseases (reviewed by Elliott and Weinstock, 2009; Harnett
and Harnett, 2010; Danilowicz-Luebert et al., 2011; McSorley and
Maizels, 2012) has excited attention on the possible molecular
products of parasites that might be applied to treatment of allergy,
autoimmunity and colitis. It is generally assumed that such molecules are released from living parasites in situ and can be collected
as excretory-secretory (ES) products from helminths cultivated
in vitro (Hewitson et al., 2009). These products may exert their effects directly on cells of the host immune system, or indirectly by
invoking the immune system’s own down-regulatory mechanisms.
Helminth parasites are an evolutionarily ancient and diverse
group of metazoan organisms and yet there is a striking convergence in similar modes of immune modulation observed in clinical
and experimental studies. Parasite suppression of immunopathology involves CD4+ regulatory T cells (Tregs, either Foxp3+ or
Foxp3 ), CD8+ Tregs, regulatory B cells, IL-4-responsive cells,
TGF-b, IL-10 and Th2 cytokines (McSorley and Maizels, 2012). Thus
distantly-related parasites have independently evolved to exploit a
range of host immunoregulatory mechanisms to their own advantage, and by invoking generic suppressive pathways can also sup-
⇑ Corresponding author. Address: Institute of Immunology and Infection
Research, University of Edinburgh, Ashworth Laboratories, West Mains Road,
Edinburgh EH9 3JT, UK. Tel.: +44 1316506763.
E-mail addresses: [email protected], [email protected]
(H.J. McSorley).
press bystander responses to allergens and self-antigens (Allen and
Maizels, 2011).
The suppression of human immunopathology by live parasitic
infections is being extensively tested (Fleming, 2011; Jouvin and
Kinet, 2012), and even offered to patients on a commercial basis.
However, real practical and ethical considerations are likely to
present major obstacles to live infection therapy being commonly
used. First, there is a logistical constraint on the scale of live parasite production, which would not satisfy the demand from large
numbers of patients with allergic and autoimmune disorders. Secondly, we understand little about the variation in human responses
to helminths, although it is recognised that naturally-acquired
infections produce a spectrum of outcomes from asymptomatic
to severe pathology, which is likely to be genetically determined
(Quinnell, 2003). Perhaps most importantly, live helminth treatment is essentially empirical and is currently applied with no
known mechanism of action. Hence, there is a great need for the
definition and development of parasite-derived immunomodulators as novel therapeutic agents, with known modes of action
and understanding of responses in the genetically heterogeneous
human population.
In order to develop non-living parasite-derived therapeutic
agents, the molecular motifs that are responsible for protection
from immunopathology must first be identified, and the host pathways that are targeted likewise defined. Across a broad range of
parasite species, a substantial number of studies have now investigated the immunomodulatory mechanisms of parasite-derived soluble molecules, ranging from total mixtures of parasite extracts,
through secretory products and biochemically-isolated fractions,
to laboratory-produced recombinant proteins and synthetic
glycans (Hewitson et al., 2009; Harnett and Harnett, 2010;
0020-7519/$36.00 Ó 2013 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijpara.2012.11.011
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Danilowicz-Luebert et al., 2011; McSorley and Maizels, 2012).
These entities have been screened across a spectrum of targets
ranging from the most reductionist level of testing single molecules in vitro on individual innate and adaptive immune cell types
through to complex models of immunopathology in vivo. In the
following sections, we discuss each of these fascinating interactions in turn.
2. Innate cells
The initiating step in the adaptive immune response to infection is an antigen presenting cell (APC, usually a dendritic cell –
DC), taking up, processing and presenting antigen to T cells. DCs
upregulate expression of surface ligands and soluble mediators
which activate antigen-specific T cells through their costimulatory and cytokine receptors. This interaction can also direct the
qualitative nature of the response, for example towards a
dominant Th1 or Th2 mode (Moser and Murphy, 2000), or indeed into the regulatory pathway of Foxp3+ Tregs (Yamazaki
et al., 2006).
Many parasite products can interfere with this process, resulting in an anergic or tolerogenic DC phenotype, or preventing the
emergence of an inflammatory Th1/17 outcome. Human or mouse
DCs, when cultured with Schistosoma mansoni Soluble Egg Antigen
(SEA), do not undergo classical maturation of costimulatory ligand
expression, but can induce Th2 responses in vitro or when transferred to a naïve host, in a MyD88- and IL-4-independent manner
(Jankovic et al., 2004). Similarly, injection of Nippostronglyus brasiliensis adult (Holland et al., 2000) or larval (Marsland et al., 2005) ES
(NES) products induces a Th2 response in an IL-4-, IL-5- and B cellindependent but class II MHC-dependent manner (Holland et al.,
2005). As in the case with SEA, Th2 induction can be replicated
in vivo by administration of NES-pulsed DCs (Balic et al., 2004)
but not basophils (Smith et al., 2012). Similarly, Fasciola hepatica
ES-pulsed DCs can drive Th2 differentiation of T cells in vitro (Falcon et al., 2010).
The Th2-inducing effects of parasite products are dominant
even if helminth antigen-pulsed DCs are cocultured with a strongly
proinflammatory stimulus such as lipopolysaccharide (LPS) (Everts
et al., 2009; Jankovic et al., 2004). Indeed, suppression of the
inflammatory (Th1) pathway is a common feature of helminth
products, including ES from Heligmosomoides polygyrus (Segura
et al., 2007; Massacand et al., 2009), Echinococcus multilocularis
(Nono et al., 2012), N. brasiliensis (Massacand et al., 2009), Taenia
crassiceps (Terrazas et al., 2011), Trichinella spiralis (Aranzamendi
et al., 2012; Bai et al., 2012) and Trichuris suis (Kuijk et al., 2012),
as well as tegumental or ES antigens from F. hepatica (Hamilton
et al., 2009; Falcon et al., 2010). The suppressive activity is evident
through ablation of IL-12 production and was retained after heattreatment of products in some cases (Aranzamendi et al., 2012;
Massacand et al., 2009), indicating a role for heat-stable glycans.
Recently, the molecules responsible for these effects have begun
to be identified. The Th2-inducing ability of SEA can be partially
attributed to a single S. mansoni product: x-1, a T2 RNase glycoprotein (Everts et al., 2009; Steinfelder et al., 2009). x-1 binds to, and
is internalised by, DCs through the mannose receptor in a carbohydrate-dependent manner, and x-1 then suppresses protein synthesis through degradation of intracellular RNA. This results in
suppression of costimulatory molecule and IL-12 expression; as a
consequence a Th2 response is favoured (Everts et al., 2012).
Although T2 RNases are present in other schistosomes (Zhou
et al., 2009; Young et al., 2012), and more distantly related parasitic helminths (such as Brugia malayi, Loa loa and Ascaris suum
(Hillwig et al., 2009)), it is as yet unknown whether this is a common mechanism of Th2 induction by parasites.
While x-1 disables DC function, and thereby Th1 induction, by
suppression of global protein expression, E. multilocularis ES prevents inflammatory responses by inducing DC apoptosis (Nono
et al., 2012). A similar phenomenon occurs in human DCs cocultivated with live microfilariae (MF) of B. malayi. The pathway activated by the MF, and probably by a product released from the
parasites, involved both TNF and TRAIL signalling (Semnani et al.,
2008). Induction of apoptosis to prevent potentially damaging cellular immune responses is in fact a widely-observed effect of helminth products, as F. hepatica ES products induce both
macrophage and eosinophil apoptosis (Guasconi et al., 2012; Serradell et al., 2007), while S. mansoni SEA induces apoptosis of T cells
in a subset of infected individuals (Carneiro-Santos et al., 2000).
Other APC-modulating factors are also active on macrophages.
For instance, Strongyloides ratti ES products contain the heat-shock
proteins, Sra-HSP-17.1 and Sra-HSP-17.2, which bind monocytes,
macrophages and intestinal epithelial cells, and induce IL-10 production by blood monocytes (Younis et al., 2011). Furthermore, a
product of the trematode F. hepatica, called FhHDM-1 (F. hepatica
Helminth Defense Molecule-1), binds LPS to prevent it stimulating
inflammatory responses (Robinson et al., 2011). FhHDM-1 also
incapacitates macrophage vacuolar ATPases, resulting in suppression of endosome acidification and defective antigen presentation
(Robinson et al., 2012). Interestingly this protein, which shows
homology to human cathelicidins, has homologues in many other
human-infective trematodes including the schistosomes (Robinson
et al., 2011), so it may be a common trematode immunomodulator.
Peroxiredoxin molecules from F. hepatica and S. mansoni also show
Th2-inducing ability and induce alternative activation of macrophages (Donnelly et al., 2008). This activation phenotype is associated with Th2 responses and can be immunosuppressive (Gordon,
2003).
As mentioned above, many of the suppressive functions of parasite products are heat-stable, indicating they may be of carbohydrate nature. Elucidation of immunomodulatory carbohydrates
from helminths has been hindered by a lack of tools for identification, manipulation and production of these molecules, however recent studies have begun to address this area (Maizels and
Hewitson, 2012). The lacto-N-fucopentaose III (LNFPIII) carbohydrate, which is present in S. mansoni egg secretions, induces alternative activation of macrophages in an IL-4R-independent manner
(Atochina et al., 2008; Bhargava et al., 2012), as well as skewing responses towards Th2 (Harn et al., 2009), and inducing IL-10 production from macrophages and DCs (Bhargava et al., 2012). The
LNFPIII glyan contains Lewisx motifs, which are thought to be
responsible for its function by signalling through C-type lectin
receptors (Harn et al., 2009). Human breast milk also contains
LNFPIII, where it is thought to have similar immunomodulatory effects as in schistosome secretions (Bhargava et al., 2012). Furthermore, a recent report showed that chitohexaose, a glycan present
on products from filarial nematodes such as Setaria digitaria and
Brugia pahangi, competes for binding to TLR-4, suppressing LPS responses and inducing alternative activation of macrophages (Panda
et al., 2012), and may represent a common heat-stable parasite-derived suppressor of TLR signalling. Thus a range of molecular products from diverse parasites share a common ability to block
inflammatory responses and induce Th2 through modulation of
DC and macrophage stimulation.
Basophils are innate cells capable of producing large amounts of
IL-4 after cross-linking of surface-bound IgE. This normally occurs
only in the presence of circulating antigen-specific IgE, following
a Th2-dominated response to a parasite. However, schistosomes exploit this mechanism to induce IL-4 release by basophils even in a
primary infection, prior to the development of a strong IgE response
against parasite antigens. IPSE/a-1 is a protein produced by S. mansoni eggs which cross-links endogenous surface-bound IgE on baso-
H.J. McSorley et al. / International Journal for Parasitology 43 (2013) 301–310
phils in an antigen non-specific manner. This interaction leads to
robust production of IL-4 and amplifies the Th2 response around
deposited eggs during S. mansoni infection (Schramm et al., 2007).
In schistosome infections, the initial Th1-dominated immune response to schistosomes switches to Th2 on egg deposition (Pearce
and MacDonald, 2002). This switch may be advantageous to the
parasite as the Th2 bias is thought to facilitate either or both egg
transit into the intestinal lumen and tissue repair of resulting lesions. If the switch to Th2 does not occur, as in IL-4/IL-13 double
deficient mice, acute mortality results (Fallon et al., 2000). In the
later stages of chronic S. mansoni infection, however, the Th2
response is downregulated, suppressing damage to the parasite
and fibrosis in the host. In chronic S. mansoni or Litomosoides
sigmodontis infection, basophils are found to be hyporesponsive to
stimulation, by a largely IL-10-dependent mechanism. When L.
sigmodontis ES products were added to normal basophils in vitro,
they were also rendered hyporesponsive (Larson et al., 2012). In
contrasting ways, therefore, helminth products can ‘‘tune’’ basophil
responses to optimise their own (and their host’s) survival.
Further complexity is added as both IPSE and x-1 have recently
been shown to be directly toxic to hepatocytes in vitro, likely promoting the liver pathology seen in schistosome infection (Abdulla
et al., 2011). IPSE also has a mammalian cell internalisation sequence and DNA-binding ability, so may modulate intracellular
signalling events and even directly influence host gene expression
(Kaur et al., 2011). These data indicate that even a single helminth
product can have multiple effects, depending on cell type and
context.
A similar contrast is seen in eosinophil responses; most helminth infections and many helminth ES materials stimulate eosinophilia, however during mouse models of asthma one of the major
features of suppression by helminth infection is reduced eosinophilia (as discussed in Section 5, below). In particular, certain ES
products can directly suppress eosinophil responses. For instance,
Necator americanus ES products contain a protease which cleaves
and inactivates eotaxin, preventing the recruitment of eosinophils
(Culley et al., 2000), while H. polygyrus ES (HES) products prevent
eosinophilia in allergen-sensitised mice (McSorley et al., 2012). In
the case of N. americanus, the Ancylostoma secreted protein
(ASP)-2 ES protein has neutrophil chemoattractant functions, and
has a charge distribution similar to mammalian chemokines (Asojo
et al., 2005; Bower et al., 2008). Thus N. americanus may suppress
the recruitment of potentially damaging eosinophils while encouraging the recruitment of ineffective neutrophils.
3. T cells
Adaptive immune responses are orchestrated by CD4+ T cells,
and many studies have addressed immunomodulatory effects of
parasite products on T cells, effects which are exerted through a
variety of direct and indirect pathways. The most prominent indirect effect is through altering DC function. DCs exposed to ES products from T. spiralis or E. multilocularis not only lose their
responsiveness to LPS (as discussed above) but switch to inducing
Th2 and Foxp3+ Treg cells in vitro (Gruden-Movsesijan et al., 2011;
Aranzamendi et al., 2012; Nono et al., 2012). Likewise, in DC-T cell
cocultures, x-1 from S. mansoni SEA can induce Foxp3+ Treg,
through induction of TGF-b and retinoic acid-activating enzymes
(Zaccone et al., 2011). As well as inducing Th2 responses when
transferred in vivo, HES product-pulsed DCs, when cultured with
T cells, suppress both IFN-c and IL-4 in favour of IL-10 and confer
a suppressive phenotype on T cells, although in this study they remained Foxp3-negative (Segura et al., 2007).
More direct effects of ES materials on T cells are evident in the
ability of HES products to induce Foxp3 expression in naïve T cells
303
even in the absence of DCs or other accessory cells (Grainger et al.,
2010). Induced Foxp3+ T cells are functional and, when transferred
to uninfected mice, protect against airway allergy. Notably, in vitro
conversion of naïve T cells is effected by ligation of the TGF-b
receptor on T cells, indicating that HES products contain a molecular mimic of this mammalian suppressive cytokine. This activity
is, moreover, not unique to HES products as ES products from the
related ruminant nematode, Teladorsagia circumcincta, display a
similar Treg-inducing property. In a distinct fashion, ES products
from Spirometra mansoni has been shown not to directly induce
Tregs, but to enhance their suppressive function in vitro (Kim
et al., 2012a).
Suppression of early innate responses and induction of Tregs
specific to helminth and bystander antigens suggests the intriguing
possibility that helminth products could be used to induce lasting
suppression and/or tolerance to potentially pathogenic allergens or
autoantigens.
4. The hygiene hypothesis
Almost 25 years ago, Strachan proposed that exposure to infections in early life protected children against airway allergy in the
form of seasonal rhinitis (Strachan, 1989). His original ‘Hygiene
Hypothesis’ suggested that early-life infections stimulated correct
development of the immune system and their absence predisposed
towards hyperactivity and inappropriate immune responses such
as those seen in allergy. The role of helminth infections in this
interaction has received much interest as these infections were
common in the developed world up to a century ago but have subsequently been largely eradicated. Over this same time period, an
epidemic of immunopathological diseases such as allergic asthma
has affected the developed nations. Epidemiological studies of atopy (Feary et al., 2011) or asthma (Leonardi-Bee et al., 2006) suggest
that current parasitic infection has a protective effect. Hence, the
protective effect of infections may not only be exerted in at an
early age but by acquiring infections in later life. Subsequently,
the Hygiene Hypothesis was further extended to other examples
of immunopathology such as autoimmunity and inflammatory bowel disease (IBD) (Elliott and Weinstock, 2012).
This theory has led to a series of clinical trials and studies of live
parasitic infection in individuals with IBD such as Crohn’s disease
(Summers et al., 2003, 2005a; Croese et al., 2006), ulcerative colitis
(Summers et al., 2003, 2005b; Broadhurst et al., 2010) or coeliac
disease (Daveson et al., 2011; McSorley et al., 2011); autoimmune
diseases such as multiple sclerosis (Correale and Farez, 2007, 2011;
Correale et al., 2008; Fleming et al., 2011; Benzel et al., 2012); and
allergic diseases such as seasonal rhinitis (Blount et al., 2009; Feary
et al., 2009; Bager et al., 2010). Furthermore, mouse models of
immunopathological disease have confirmed the protective effect
of helminth infection (reviewed in McSorley and Maizels, 2012)
To identify the molecules and mechanisms used by parasites to
suppress these responses, parasite products have been administered in a range of these immunopathology models, to attempt
to replicate suppression in parasitic infection.
5. Airway allergy (asthma)
Asthma is an allergic disease that can be modelled in mice by
administration of a model allergen (such as ovalbumin, OVA) in
an alum adjuvant (sensitisation), followed by recall of a Th2 response by allergen administration to the airways (challenge),
resulting in recruitment of eosinophils, production of Th2 cytokines
and airway hyperresponsiveness to stimuli (Bates et al., 2009). A
range of helminth products are able to interfere with the development or expression of allergic reactions. Thus, administration of A.
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suum adult worm antigen (Lima et al., 2002), SEA (Yang et al., 2007),
NES products (Trujillo-Vargas et al., 2007), Toxascaris leonina ES
products (Lee et al., 2008) or HES products (McSorley et al., 2012)
at sensitisation result in suppression of the allergic response at
challenge. Using NES products, the mechanism of suppression
was found to be independent of IL-10 and TLR 2 or 4 signalling,
but required conformationally-intact protein as activity was ablated on heat treatment (Trujillo-Vargas et al., 2007). In contrast,
the suppressive factor in HES products, when given at sensitisation,
was heat-stable (McSorley et al., 2012), and could not be replicated
by administration of mammalian TGF-b at the level of activity
found in HES products (Grainger et al., 2010). As these products
modulate the recall response when given at the initiation of the
allergic immune response, it seems likely they are interfering with
the early events in antigen presentation, T cell proliferation or Th2
differentiation.
HES products can also suppress airway inflammation when
administered into the airways at OVA challenge (McSorley et al.,
2012), in a setting which reflects inhibition of an established Th2
response. Using this protocol, suppression was ablated by heat
treatment of HES products, indicating it is due to a different product than that which suppresses when HES products were administered at sensitisation, and that the heat-labile product suppresses
cellular recruitment or Th2 effector mechanisms.
Recent studies on allergic airway inflammation have started to
address the immunomodulatory effects of individual parasite-derived molecules. The first to show this was a study of suppressive
effects of whole body extract of A. suum (Lima et al., 2002), which
could be replicated with the purified single product, PAS-1 (Itami
et al., 2005). Likewise, Acanthocheilonema viteae recombinant
Av17 cystatin can suppress allergic airway pathology in a macrophage- and IL-10-dependent manner. Similar to administration of
HES products in this model, this suppression was maintained
whether Av17 was administered with sensitisation injections, or
after them, prior to challenge (Schnoeller et al., 2008).
Suppression of Th2 responses would be advantageous to most
parasites, as this is the mode of response which most efficiently
mediates their ejection. Future work should give valuable insights
into the mechanisms of suppression of Th2 responses against both
parasites and bystander antigens both at the level of Th2 induction
(by administering parasite products with the OVA sensitisation),
and established anti-parasite Th2 responses (by administering parasite products at OVA-airway challenge). A possibility that should
be considered is whether helminth molecules induce a competing
Th2 response, as many parasite products themselves induce potent
Th2 responses in vivo (Balic et al., 2004; Dowling et al., 2011;
Zaccone et al., 2011) and in the case of administration of NES
products, an allergic-type response developed to the ES antigens
themselves (Trujillo-Vargas et al., 2007).
6. Autoimmunity
Most autoimmune diseases involve hyperreactivity of the Th1
and Th17 effector subsets. While it is not so obviously advantageous to the parasite to suppress these responses (as opposed to
parasite-toxic Th2 responses), an indirect benefit may be to create
a less inflammatory environment, e.g. in the intestinal tract, for
parasite residence.
Suppression of bystander Th1 and Th17 responses has been reported in a range of autoimmune diseases as well as in immunopathological contexts such as colitis. A commonly used model of
autoimmunity is the type 1 diabetes-like disease which spontaneously arises in Non-Obese Diabetic (NOD) mice, which results in
progressive destruction of insulin-producing islets in the pancreas
(Anderson and Bluestone, 2005). Litomosoides sigmodontis adult
worm antigen and S. mansoni SEA and soluble worm antigen preparation (SWAP) have each been shown to suppress autoimmune
responses in NOD mice (Zaccone et al., 2003, 2009, 2010; Hubner
et al., 2009). Suppression of diabetic pathology by SEA was associated with expansion of invariant Natural Killer T cells (iNKT cells,
which are deficient in NOD mice), Tregs and alternatively activated
macrophages (Zaccone et al., 2003, 2009, 2010). This may be a
reflection of a physiological mechanism to minimise pathology in
schistosome infection, as expansion of iNKT cells, Tregs and alternatively activated macrophages have all been found to be important in regulating the anti-schistosome immune response
(Mallevaey et al., 2007; Wilson et al., 2007).
Trichuris suis live infection has shown some efficacy in treating
human multiple sclerosis (Fleming et al., 2011) and administration
of products from T. suis or the related parasite, Trichinella spiralis,
show suppression of pathology in the mouse model of multiple
sclerosis, known as Experimental Autoimmune Encephalomyelitis
(EAE) (Kuijk et al., 2012). Administration of SEA also suppresses
EAE pathology, through skewing the immune responses from
Th1/Th17 to Th2 (Zheng et al., 2008). As mentioned above, parasite
products are capable of modulating DCs to induce Th2 responses,
and suppress the inflammatory Th1-inducing phenotype. Intriguingly, it was recently shown that F. hepatica total extract is capable
of skewing CpG-stimulated DCs to a tolerogenic phenotype which,
when transferred to collagen-immunised mice, could suppress collagen-induced arthritis (Carranza et al., 2012). Most notably, ES-62
from the rodent filarial parasite, A. viteae, has shown efficacy in
models of arthritis, as will be discussed by Rzepecka et al. (2012).
7. IBD and colitis
IBD in humans include Crohn’s disease, which affects all parts of
the gastrointestinal tract; and ulcerative colitis, which affects only
the colon (Baumgart and Carding, 2007). Both of these diseases
have autoimmune characteristics, but a role for intestinal barrier
disruption and immune responses to commensal bacteria has also
been proposed, especially in Crohn’s disease (Baumgart and Sandborn, 2012). These diseases are presently incurable and treatment
consists of immune suppression and, in extreme cases, bowel
resection. Another common immune-mediated disease of the
intestine is coeliac disease, caused by immune responses both to
oral gluten and to the host enzyme which digests gluten, tissue
transglutaminase (Di Sabatino and Corazza, 2009).
There are several mouse models of inflammatory IBD, which can
be divided into those which depend on degradation of the intestinal epithelial barrier (such as Dextran Sulphate Sodium (DSS), or
di- or tri-nitrobenzene sulphonic acid (DNBS or TNBS) colitis) (Wirtz et al., 2007) or those which depend on perturbation of the immune system leading to initiation of an inflammatory T cell
response to commensals (such as the T cell transfer (Ostanin
et al., 2009) or IL-10-deficient (Berg et al., 2002) models of colitis).
It is worth noting that of these models, DSS colitis is wholly dependent on innate responses to commensal bacteria (it is ablated in
germ-free mice), and is largely T cell-independent (similar progression of disease is seen in T cell-deficient mice) (Wirtz et al., 2007),
while all other models are entirely dependent on T cell responses.
In the T cell-dependent model of colitis engendered by TNBS
exposure, whole worm extract of S. mansoni or Ancylostoma caninum
ES products, when given at TNBS administration, can suppress colitic pathology (Ruyssers et al., 2009). Likewise, ES products of a related hookworm, Ancylostoma ceylanicum, suppress pathology in
the DSS model (Cancado et al., 2011). In DNBS colitis, products of
the tapeworm, Hymenolepis diminuta, suppress pathology (Johnston
et al., 2010), and induce alternative activation of macrophages.
Transfer of in vitro-derived alternatively activated macrophages to
H.J. McSorley et al. / International Journal for Parasitology 43 (2013) 301–310
naïve recipients also suppressed colitis, thus providing a link between suppression of pathology and macrophage phenotype (Hunter et al., 2010).
An interesting range of molecular species has been associated
with suppression of IBD pathologies. For example, T. spiralis muscle-stage antigen extract, when administered submucosally in
the rectum, can suppress DNBS colitis and this suppression was
associated with an emergence of Th2 (IL-13) and regulatory
(TGF-b) cytokine production in the colon (Motomura et al., 2009).
The protective effect of T. spiralis antigens in colitis could be recapitulated with administration of recombinant TsP53, which induced IL-10 and TGF-b (Du et al., 2011). Likewise, SEA suppresses
colitis and this activity can be replicated using the S. mansoni products Sm22.6, PIII and Sm29. Perhaps surprisingly IPSE, a known
immunomodulatory and Th2-amplifying molecule within SEA,
has no effect in this system, indicating that specific modulators target different inflammatory pathways in the host (Cardoso et al.,
2010).
Another defined molecule with anti-colitic activity is found in
Toxascaris leonina, an intestinal parasite of dogs, which encodes
the galectin-9 homologue, Tl-gal. Similar to that seen with TsP53
administration (Du et al., 2011), when the T. leonina galectin homologue was administered in the DSS colitis model, suppression of
pathology was seen, together with induction of IL-10 and TGF-b
(Kim et al., 2010). Galectins are widely expressed by helminth parasites and frequently found in the ES material (Hewitson et al.,
2009), while in mammals there are many instances of galectins
acting to suppress immunological reactions (Rabinovich et al.,
2002). The broader role of galectins as parasite immunomodulators
will be discussed in greater detail in the Section 8.
In addition to galectins, the cystatin (cysteine protease inhibitors) family is also associated with helminth immunomodulation
(Hartmann and Lucius, 2003; Gregory and Maizels, 2008). The filarial nematode, A. viteae, and the liver fluke, Clonorchis sinesis, both
produce cystatins which suppress pathology in the DSS colitis
model and induce IL-10-producing macrophages (Jang et al.,
2011; Schnoeller et al., 2008). Therefore cystatins (present in many
parasite secretions, including those of H. polygyrus (Hewitson et al.,
2011b)) may be common parasite immunomodulators that have
evolved in these evolutionarily very distinct lineages.
Although the ability of H. polygyrus to suppress pathology in
colitis through interactions with the innate and adaptive immune
system has been well investigated (Elliott et al., 2004; Sutton
et al., 2008; Blum et al., 2012), HES products have not to date been
tested. This may be a rich seam for novel therapeutic agents in IBD.
8. Molecular characterisation of H. polygyrus ES material
Motivated by the findings that adult parasite secretions contain
both heat labile (TGF-b-mimic mediated generation of suppressive
Treg cells) and heat stable (inhibition of allergic inflammation
in vivo) immunomodulatory components, we have embarked on
a proteomic and glycomic characterisation of adult HES. More than
350 proteins present in adult HES have been identified, many of
which are shared with the secretions of the tissue-dwelling L4
(Hewitson et al., 2011b; our unpublished data). Proteomic studies
have revealed that HES products are very extensively distinct from
adult worm somatic extract, with preferential secretion of several
families of proteins, in particular members of the venom-allergen-like (VAL) superfamily, apyrases, lysozymes, acetylcholinesterases, proteases and protease inhibitors (Hewitson et al.,
2011b). Secretion of such proteins has been previously noted in
other strongylid nematodes, including those of veterinary (Haemonchus contortus (Yatsuda et al., 2003); T. circumcincta (Nisbet
et al., 2010)) and medical importance (hookworms; (Mulvenna
305
et al., 2009)), suggesting H. polygyrus is a useful laboratory model
for these important diseases.
The most striking feature of adult HES products are the large
number (25) of VAL proteins, containing a characteristic
cysteine-rich motif also found in sperm coat protein (SCP, pfam domain PF00188; http://www.ebi.ac.uk/goldman-srv/pandit/pandit.cgi?action=browse&fam=PF00188;
http://pfam.sanger.ac.uk/
family/PF00188). Originally identified as dominant secretions of
larval hookworms, termed Ancylostoma secreted proteins, or ASPs
(Hawdon et al., 1996), it is now clear that adult worms also secrete
large numbers and amounts of these proteins. Proteins of this family
have been previously trialled in humans as vaccine candidates,
although this has proved problematic owing to their allergenic nature (Diemert et al., 2012). Because the secreted VAL proteins of H.
polygyrus and other helminths (Mulvenna et al., 2009; Cantacessi
and Gasser, 2012) have a high degree of sequence diversity, doubt
has been raised as to whether they share an evolutionarily conserved function such as immunomodulation, or whether the SCP domain simply represents a versatile protein module with which
distinct functions can be built (Cantacessi and Gasser, 2012). Nevertheless, some immunomodulatory functions have been ascribed to
VAL proteins including neutrophil chemoattraction (Asojo et al.,
2005; Bower et al., 2008). Perhaps surprisingly, VAL proteins have
also been shown to have Th1 adjuvant-promoting abilities in vivo
(He et al., 2009) through direct interaction with antigen presenting
cells and TLR triggering.
VAL proteins are characterised by the presence of one or two
SCP domains, and both single- and double-domain VALs are present in HES products. Analysis of antibody binding has revealed that
both classes of VAL protein are the immundominant target of IgG1
antibodies in primary and secondary H. polygyrus infection (Hewitson et al., 2011a), an antibody isotype previously shown to be protective in this infection (McCoy et al., 2008). Additionally, the two
SCP domains of the double domain VAL proteins are connected by a
20–40 amino acid linker region rich in serine and threonine residues, which are decorated with a common O-linked sugar (named
‘‘glycan A’’ (Hewitson et al., 2011a)), which represents the dominant IgM target in infection.
Amongst other candidate immunomodulators, HES products
contain a cystatin, as mentioned previously. As cystatins produced by A. viteae and C. sinesis are protective in allergic airway
pathology and colitis (Schnoeller et al., 2008; Jang et al., 2011),
this target may warrant more study. HES products also contain
three members of another protease inhibitor family, the serpins.
Serpins are a family of proteins which suppress serine proteases
such as neutrophil elastase and cathepsin G, and are produced
by a range of parasites (Zang and Maizels, 2001; Molehin et al.,
2012). Elastase and cathepsin G are responsible for activation of
the ‘alarmin’ cytokine, IL-33 (Lefrancais et al., 2012). IL-33 induces innate lymphoid cells, alternatively activated macrophages
and eosinophilia during the initialisation of innate type 2 responses (Koyasu and Moro, 2011). Thus serpins may be important
in suppressing the very earliest events in Th2 induction during
parasitic infections.
Another potential immunomodulatory family in HES products
are the apyrases, four of which were detected. Apyrases convert
immunostimulatory ATP to more tolerogenic AMP and adenosine,
and whilst extracellular ATP can promote lung and gut inflammation, apyrases are able to prevent this (Idzko et al., 2007). In the
intestine, ATP is required for the generation of pro-inflammatory
Th17 cells (Atarashi et al., 2008) and promotes the conversion of
Treg cells into effector Th17 cells (Schenk et al., 2011), both of
which processes seem likely to be limited by apyrase enzymes.
Functional apyrases have also been identified as potential immunomodulators from other parasites, including T. circumcincta
(Nisbet et al., 2011).
306
H.J. McSorley et al. / International Journal for Parasitology 43 (2013) 301–310
Multiple families of carbohydrate-binding proteins are found in
HES products: two chitinase/chitin-binding domain proteins, five
galectins and three C-type lectins. Particularly prominent are the
chitinase proteins, which are of interest as immunomodulators as
chitin induces Th2 responses and high levels of host chitinases
are produced during active Th2 responses such as asthma (Sutherland et al., 2009). Thus, chitinases in HES products could result in
lower levels of parasite-derived chitin and a reduced Th2 response.
Galectins are multifunctional immune mediators in the mammalian immune system, however a feature common to mammalian
galectins 1, 2, 3, 4, 8 and 9 is the ability to cause apoptosis in activated T cells, while mammalian galectins 1 and 9 are both expressed by mouse Tregs and selectively cause apoptosis of Th1
(but not Th2) cells (Liu et al., 2012). As mentioned previously, a
galectin-9 homologue from T. leonina protects against colitis (Kim
et al., 2010). Thus, H. polygyrus and other parasites may produce
galectins to inhibit activated T cell (especially Th1) responses.
HES products also contain two fatty acid/retinol binding proteins. As the downstream metabolite of retinol, retinoic acid, is
important in the intestine for inducing Tregs and suppressing
Th17 differentiation, it is tempting to speculate that these could
potentiate Treg induction (Elias et al., 2008). More broadly, retinoic
acid deficiency results in a generalised impairment of immune
responsiveness (Hall et al., 2011) and hence dampening of immunity could result if, as reported (Comley and Jaffe, 1983), helminths
are able to sequester this molecule. Retinol-binding proteins are
found in many parasitic helminths including Taenia solium, Ascaris
spp., Toxocara canis and filarial parasites including B. malayi and
Loa loa (Esteves and Ehrlich, 2006; Kim et al., 2012b). Fatty-acid
binding proteins may well function in parasite acquisition of host
molecules, or to deliver them to target cell types, but their role
in modulation of the host immune response remains to be
investigated.
Eight lysozymes have been identified in HES products. Lysozymes degrade peptidoglycan in bacterial cells walls (especially
Gram positive bacterial cells walls), and as H. polygyrus infection
is known to change the commensal balance in the intestine (Walk
et al., 2010), these could be a potential mediator. Growing interest
has developed in how commensals affect immune responses
(Molloy et al., 2012), therefore this could be a mechanism by which
the parasite skews immune responses in the intestine. Evidence
that this is advantageous to the parasite comes from recent data
showing that the higher the levels of Lactobacillus spp. in the intestine, the greater the adult worm number (Maizels et al., 2012).
A new insight into the biology of H. polygyrus infections is also
afforded by analysis of the ES products from immature L4s developing in the intestinal tissue, beneath the muscular layer. Proteomic characterisation identifies a substantial overlap between the
secretomes of adult and L4 parasites, although there is a relative
expansion of VAL family members in the lumina-dwelling adult
repertoire (Hewitson et al., unpublished data). In contrast, other
gene families are greatly expanded in the tissue-dwelling L4.
Among these are proteins containing a 36-amino acid motif with
six cysteines in a distinct configuration (SXC), first noted in the
ES of the nematode T. canis (Gems et al., 1995) and independently
in a potassium-blocking toxin of a marine anemone, (Tudor et al.,
1996). Interestingly, the sea anemone toxin can block activation
in mammalian T cells, and itself is being tested as a potential therapeutic agent for autoimmune disease (Chi et al., 2012). Thus, the
ability of helminth SXC-containing proteins to act in a similar manner urgently needs to be assessed.
Finally, HES products contain large numbers of previously
uncharacterised proteins, termed novel secreted proteins (NSPs),
many of which cluster into distinct NSP families. Although the
function (immunomodulatory or otherwise) of these proteins remains unknown, their presence in HES products (and often not in
the parasite somatic extract) implies some interaction with the
host.
Clearly there are multiple potential immunomodulatory protein
families in HES products (Table 1), however many proteins in HES
products are also highly glycosylated and the immunosuppressive
role of individual HES-derived glycans has not yet been addressed.
A role for glycans in HES product immunosuppression is implied by
the heat-stability of the suppressive factor in a mouse model of
asthma (McSorley et al., 2012). On-going glycomic characterisation
of purified VAL proteins has revealed the presence of several short
O-glycans, a subset of which are likely to be the ‘‘glycan A’’ antigen
(J Hewitson, unpublished observations). Although an immunomodulatory role for this sugar has not yet been described, it is detectable in the serum of infected mice, indicating its potential (and
that of other parasite secretions) to traffic to, and influence, immune cells in distal sites (Herbst et al., 2012).
Table 1
Immunomodulatory protein families contained in Heligmosomoides polygyrus Excretory/Secretory products.
Protein family
Immunological effects
Reference
Apyrase
Degrade inflammatory ATP
Suppress pathology in models of asthma
ATP induces Th17 cells in the gut
Chitin promotes Th2
Chitinase reduces Th2?
Inhibit antigen processing
Suppress pathology in models of asthma and colitis
Apoptosis of activated T cells, especially Th1 cells
Degrade bacterial cell walls
Change commensal balance?
Retinol induces Tregs, suppresses Th17
Reduced immune responsiveness in retinol deficiency
Inhibit serine proteases – e.g. neutrophil elastase/cathepsin G
Inhibit IL-33 activation?
Allergenic
Vaccine candidates
Neutrophil chemoattraction
Th1-promoting
Suppress T and B cell proliferation
Induce Foxp3+ Tregs
Suppress APC maturation/prevents TLR signaling
Idzko et al. (2007)
Chitinase/chitin-binding
Cystatin
Galectin
Lysozyme
Retinol-binding
Serpin
VAL/ASP/SCP
TGF-b mimic
Atarashi et al. (2008)
Sutherland et al. (2009) and Da Silva et al. (2010)
Manoury et al. (2001)
Schnoeller et al. (2008) and Jang et al. (2011)
Kim et al. (2010), Liu et al. (2012)
Dommett et al. (2005)
Walk et al. (2010)
Esteves and Ehrlich (2006), Elias et al. (2008) and Kim et al. (2012b)
Zang et al. (1999) and Molehin et al. (2012) Lefrancais et al. (2012)
Diemert et al. (2012)
Asojo et al. (2005)
Bower et al. (2008)
He et al. (2009)
Grainger et al. (2010)
Tregs, regulatory T cells; VAL, venom-allergen-like; ASP, Ancylostoma secreted protein; SCP, sperm coat protein; APC, antigen presenting cell; TLR, toll-like receptor.
H.J. McSorley et al. / International Journal for Parasitology 43 (2013) 301–310
9. Helminth therapies: towards clinical application
The wealth and diversity of helminth molecules with potential
for the therapy of immune dysfunctions in humans present an
enormous resource for future applications, matched only by the
scale of challenges that must be met to reach a clinically-approved
therapy. At this early stage, most modulators under study are parasite proteins, which may prove too immunogenic in the human
for use without modification. In addition, many are derived from
animal model parasites, and the efficacy of proteins optimally
adapted to animal species requires verification in the human setting. For both reasons, it is likely that pathways of immunomodulation need to be carefully mapped, so that parasite effects can be
reproduced by small molecules or humanised reagents containing
the minimal effective parasite-encoded motifs required to interact
with key host molecules.
In this context, trials under way with live helminth therapies
are both encouraging and informative. The success, even on a small
scale, of live helminth treatments would validate the ‘‘Hygiene
Hypothesis’’ as the rationale for using helminth molecules to alleviate immunopathologies, and a careful immunological analysis of
recipients of helminth therapy will provide important pointers to
the immunosuppressive pathways that may be activated in these
patients. It will be essential to consider each species (e.g. T. suis
versus N. americanus) as very different systems, as the variety of
molecules and mechanisms discussed above argues strongly that
each parasite is exquisitely adapted to a precise and probably unique series of immunological interactions. By breaking down the
complexity of these interactions into defined, targeted effects, future molecular therapies based on helminth-derived modulators
should achieve the goal of providing new pharmacological agents
which can be applied at appropriate doses and intervals to control
specific immunopathologies in human patients.
10. Conclusion
Parasitic helminths produce a myriad of immunomodulatory
molecules to suppress anti-parasite and immunopathological responses at multiple levels, from the very early initiating events
in innate immunity to the final effector mechanisms in established
adaptive responses. Interestingly, helminth products can block
both Th1/Th17-mediated inflammation and Th2-dependent
pathologies, giving them the potential to treat the full range of human immunological disorders. Moreover, helminth infections are
themselves chronic diseases, sharing a time-scale and dynamic
with many of the autoimmune and allergic conditions that we seek
to treat. If parasites have evolved to also manipulate the immune
response in a state of chronic stimulation, the molecules involved
may be particularly apposite for human therapy. Such prospects
remain to be fully tested, but the weight of evidence in both humans and animal models gives us grounds for real optimism towards new molecular therapies from helminths.
Acknowledgements
The authors thank the Wellcome Trust, UK and the American
Asthma Foundation for funding.
References
Abdulla, M.H., Lim, K.C., McKerrow, J.H., Caffrey, C.R., 2011. Proteomic identification
of IPSE/alpha-1 as a major hepatotoxin secreted by Schistosoma mansoni eggs.
PLoS Negl. Trop. Dis. 5, e1368.
Allen, J.E., Maizels, R.M., 2011. Diversity and dialogue in immunity to helminths.
Nat. Rev. Immunol. 11, 375–388.
Anderson, M.S., Bluestone, J.A., 2005. The NOD mouse: a model of immune
dysregulation. Annu. Rev. Immunol. 23, 447–485.
307
Aranzamendi, C., Fransen, F., Langelaar, M., Franssen, F., van der Ley, P., van Putten,
J.P., Rutten, V., Pinelli, E., 2012. Trichinella spiralis-secreted products modulate
DC functionality and expand regulatory T cells in vitro. Parasite Immunol. 34,
210–223.
Asojo, O.A., Goud, G., Dhar, K., Loukas, A., Zhan, B., Deumic, V., Liu, S., Borgstahl, G.E.,
Hotez, P.J., 2005. X-ray structure of Na-ASP-2, a pathogenesis-related-1 protein
from the nematode parasite, Necator americanus, and a vaccine antigen for
human hookworm infection. J. Mol. Biol. 346, 801–814.
Atarashi, K., Nishimura, J., Shima, T., Umesaki, Y., Yamamoto, M., Onoue, M., Yagita,
H., Ishii, N., Evans, R., Honda, K., Takeda, K., 2008. ATP drives lamina propria
T(H)17 cell differentiation. Nature 455, 808–812.
Atochina, O., Da’dara, A.A., Walker, M., Harn, D.A., 2008. The immunomodulatory
glycan LNFPIII initiates alternative activation of murine macrophages in vivo.
Immunology 125, 111–121.
Bager, P., Arnved, J., Ronborg, S., Wohlfahrt, J., Poulsen, L.K., Westergaard, T.,
Petersen, H.W., Kristensen, B., Thamsborg, S., Roepstorff, A., Kapel, C., Melbye,
M., 2010. Trichuris suis ova therapy for allergic rhinitis: a randomized, doubleblind, placebo-controlled clinical trial. J. Allergy Clin. Immunol. 125 (123–130),
e121–123.
Bai, X., Wu, X., Wang, X., Guan, Z., Gao, F., Yu, J., Yu, L., Tang, B., Liu, X., Song, Y., Radu,
B., Boireau, P., Wang, F., Liu, M., 2012. Regulation of cytokine expression in
murine macrophages stimulated by excretory/secretory products from
Trichinella spiralis in vitro. Mol. Cell. Biochem. 360, 79–88.
Balic, A., Harcus, Y., Holland, M.J., Maizels, R.M., 2004. Selective maturation of
dendritic cells by Nippostrongylus brasiliensis-secreted proteins drives Th2
immune responses. Eur. J. Immunol. 34, 3047–3059.
Bates, J.H., Rincon, M., Irvin, C.G., 2009. Animal models of asthma. Am. J. Physiol.
Lung Cell. Mol. Physiol. 297, L401–410.
Baumgart, D.C., Carding, S.R., 2007. Inflammatory bowel disease: cause and
immunobiology. Lancet 369, 1627–1640.
Baumgart, D.C., Sandborn, W.J., 2012. Crohn’s disease. Lancet 380, 1590–1603.
Benzel, F., Erdur, H., Kohler, S., Frentsch, M., Thiel, A., Harms, L., Wandinger, K.P.,
Rosche, B., 2012. Immune monitoring of Trichuris suis egg therapy in multiple
sclerosis patients. J. Helminthol. 86, 339–347.
Berg, D.J., Zhang, J., Weinstock, J.V., Ismail, H.F., Earle, K.A., Alila, H., Pamukcu, R.,
Moore, S., Lynch, R.G., 2002. Rapid development of colitis in NSAID-treated IL10-deficient mice. Gastroenterology 123, 1527–1542.
Bhargava, P., Li, C., Stanya, K.J., Jacobi, D., Dai, L., Liu, S., Gangl, M.R., Harn, D.A., Lee,
C.H., 2012. Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and
insulin resistance through direct and indirect control of metabolic pathways.
Nat. Med. 18, 1665–1672.
Blount, D., Hooi, D., Feary, J., Venn, A., Telford, G., Brown, A., Britton, J., Pritchard, D.,
2009. Immunologic profiles of persons recruited for a randomized, placebocontrolled clinical trial of hookworm infection. Am. J. Trop. Med. Hyg. 81, 911–
916.
Blum, A.M., Hang, L., Setiawan, T., Urban Jr., J.P., Stoyanoff, K.M., Leung, J.,
Weinstock, J.V., 2012. Heligmosomoides polygyrus bakeri induces tolerogenic
dendritic cells that block colitis and prevent antigen-specific gut T cell
responses. J. Immunol. 189, 2512–2520.
Bower, M.A., Constant, S.L., Mendez, S., 2008. Necator americanus: the Na-ASP-2
protein secreted by the infective larvae induces neutrophil recruitment in vivo
and in vitro. Exp. Parasitol. 118, 569–575.
Broadhurst, M.J., Leung, J.M., Kashyap, V., McCune, J.M., Mahadevan, U., McKerrow,
J.H., Loke, P., 2010. IL-22+ CD4+ T cells are associated with therapeutic Trichuris
trichiura infection in an ulcerative colitis patient. Sci. Transl. Med. 2, 60ra88.
Cancado, G.G., Fiuza, J.A., de Paiva, N.C., Lemos Lde, C., Ricci, N.D., GazzinelliGuimaraes, P.H., Martins, V.G., Bartholomeu, D.C., Negrao-Correa, D.A., Carneiro,
C.M., Fujiwara, R.T., 2011. Hookworm products ameliorate dextran sodium
sulfate-induced colitis in BALB/c mice. Inflamm. Bowel Dis. 17, 2275–2286.
Cantacessi, C., Gasser, R.B., 2012. SCP/TAPS proteins in helminths – where to from
now? Mol. Cell. Probes 26, 54–59.
Cardoso, L.S., Oliveira, S.C., Goes, A.M., Oliveira, R.R., Pacifico, L.G., Marinho, F.V.,
Fonseca, C.T., Cardoso, F.C., Carvalho, E.M., Araujo, M.I., 2010. Schistosoma
mansoni antigens modulate the allergic response in a murine model of
ovalbumin-induced airway inflammation. Clin. Exp. Immunol. 160, 266–274.
Carneiro-Santos, P., Martins-Filho, O., Alves-Oliveira, L.F., Silveira, A.M., Coura-Filho,
P., Viana, I.R., Wilson, R.A., Correa-Oliveira, R., 2000. Apoptosis: a mechanism of
immunoregulation during human Schistosomiasis mansoni. Parasite Immunol.
22, 267–277.
Carranza, F., Falcon, C.R., Nunez, N., Knubel, C., Correa, S.G., Bianco, I., Maccioni, M.,
Fretes, R., Triquell, M.F., Motran, C.C., Cervi, L., 2012. Helminth antigens enable
CpG-activated dendritic cells to inhibit the symptoms of collagen-induced
arthritis through Foxp3+ regulatory T cells. PLoS One 7, e40356.
Chi, V., Pennington, M.W., Norton, R.S., Tarcha, E.J., Londono, L.M., Sims-Fahey, B.,
Upadhyay, S.K., Lakey, J.T., Iadonato, S., Wulff, H., Beeton, C., Chandy, K.G., 2012.
Development of a sea anemone toxin as an immunomodulator for therapy of
autoimmune diseases. Toxicon 59, 529–546.
Comley, J.C., Jaffe, J.J., 1983. The conversion of exogenous retinol and related
compounds into retinyl phosphate mannose by adult Brugia pahangi in vitro.
Biochem. J. 214, 367–376.
Correale, J., Farez, M., 2007. Association between parasite infection and immune
responses in multiple sclerosis. Ann Neurol. 61, 97–108.
Correale, J., Farez, M., Razzitte, G., 2008. Helminth infections associated with
multiple sclerosis induce regulatory B cells. Ann. Neurol. 64, 187–199.
Correale, J., Farez, M.F., 2011. The impact of parasite infections on the course of
multiple sclerosis. J. Neuroimmunol. 233, 6–11.
308
H.J. McSorley et al. / International Journal for Parasitology 43 (2013) 301–310
Croese, J., O’Neil, J., Masson, J., Cooke, S., Melrose, W., Pritchard, D., Speare, R., 2006.
A proof of concept study establishing Necator americanus in Crohn’s patients
and reservoir donors. Gut 55, 136–137.
Culley, F.J., Brown, A., Conroy, D.M., Sabroe, I., Pritchard, D.I., Williams, T.J., 2000.
Eotaxin is specifically cleaved by hookworm metalloproteases preventing its
action in vitro and in vivo. J. Immunol. 165, 6447–6453.
Da Silva, C.A., Pochard, P., Lee, C.G., Elias, J.A., 2010. Chitin particles are multifaceted
immune adjuvants. Am. J. Respir. Crit. Care Med. 182, 1482–1491.
Danilowicz-Luebert, E., O’Regan, N.L., Steinfelder, S., Hartmann, S., 2011.
Modulation of specific and allergy-related immune responses by helminths. J.
Biomed. Biotechnol. 2011, 821578.
Daveson, A.J., Jones, D.M., Gaze, S., McSorley, H., Clouston, A., Pascoe, A., Cooke, S.,
Speare, R., Macdonald, G.A., Anderson, R., McCarthy, J.S., Loukas, A., Croese, J.,
2011. Effect of hookworm infection on wheat challenge in celiac disease – a
randomised double-blinded placebo controlled trial. PLoS One 6, e17366.
Di Sabatino, A., Corazza, G.R., 2009. Coeliac disease. Lancet 373, 1480–1493.
Diemert, D.J., Pinto, A.G., Freire, J., Jariwala, A., Santiago, H., Hamilton, R.G., Periago,
M.V., Loukas, A., Tribolet, L., Mulvenna, J., Correa-Oliveira, R., Hotez, P.J.,
Bethony, J.M., 2012. Generalized urticaria induced by the Na-ASP-2 hookworm
vaccine: implications for the development of vaccines against helminths. J.
Allergy Clin. Immunol. 130 (169–176), e166.
Dommett, R., Zilbauer, M., George, J.T., Bajaj-Elliott, M., 2005. Innate immune
defence in the human gastrointestinal tract. Mol. Immunol. 42, 903–912.
Donnelly, S., Stack, C.M., O’Neill, S.M., Sayed, A.A., Williams, D.L., Dalton, J.P., 2008.
Helminth 2-Cys peroxiredoxin drives Th2 responses through a mechanism
involving alternatively activated macrophages. FASEB J. 22, 4022–4032.
Dowling, D.J., Noone, C.M., Adams, P.N., Vukman, K.V., Molloy, S.F., Forde, J., Asaolu,
S., O’Neill, S.M., 2011. Ascaris lumbricoides pseudocoelomic body fluid induces a
partially activated dendritic cell phenotype with Th2 promoting ability in vivo.
Int. J. Parasitol. 41, 255–261.
Du, L., Tang, H., Ma, Z., Xu, J., Gao, W., Chen, J., Gan, W., Zhang, Z., Yu, X., Zhou, X., Hu,
X., 2011. The protective effect of the recombinant 53-kDa protein of Trichinella
spiralis on experimental colitis in mice. Dig. Dis. Sci. 56, 2810–2817.
Elias, K.M., Laurence, A., Davidson, T.S., Stephens, G., Kanno, Y., Shevach, E.M.,
O’Shea, J.J., 2008. Retinoic acid inhibits Th17 polarization and enhances FoxP3
expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111,
1013–1020.
Elliott, D.E., Setiawan, T., Metwali, A., Blum, A., Urban Jr., J.F., Weinstock, J.V., 2004.
Heligmosomoides polygyrus inhibits established colitis in IL-10-deficient mice.
Eur. J. Immunol. 34, 2690–2698.
Elliott, D.E., Weinstock, J.V., 2009. Helminthic therapy: using worms to treat
immune-mediated disease. Adv. Exp. Med. Biol. 666, 157–166.
Elliott, D.E., Weinstock, J.V., 2012. Helminth-host immunological interactions:
prevention and control of immune-mediated diseases. Ann. N.Y. Acad. Sci. 1247,
83–96.
Esteves, A., Ehrlich, R., 2006. Invertebrate intracellular fatty acid binding proteins.
Comp. Biochem. Physiol. C: Toxicol. Pharmacol. 142, 262–274.
Everts, B., Hussaarts, L., Driessen, N.N., Meevissen, M.H., Schramm, G., van der Ham,
A.J., van der Hoeven, B., Scholzen, T., Burgdorf, S., Mohrs, M., Pearce, E.J., Hokke,
C.H., Haas, H., Smits, H.H., Yazdanbakhsh, M., 2012. Schistosome-derived
omega-1 drives Th2 polarization by suppressing protein synthesis following
internalization by the mannose receptor. J. Exp. Med. 209, 1753–1767.
Everts, B., Perona-Wright, G., Smits, H.H., Hokke, C.H., van der Ham, A.J.,
Fitzsimmons, C.M., Doenhoff, M.J., van der Bosch, J., Mohrs, K., Haas, H.,
Mohrs, M., Yazdanbakhsh, M., Schramm, G., 2009. Omega-1, a glycoprotein
secreted by Schistosoma mansoni eggs, drives Th2 responses. J. Exp. Med. 206,
1673–1680.
Falcon, C., Carranza, F., Martinez, F.F., Knubel, C.P., Masih, D.T., Motran, C.C., Cervi, L.,
2010. Excretory-secretory products (ESP) from Fasciola hepatica induce
tolerogenic properties in myeloid dendritic cells. Vet. Immunol.
Immunopathol. 137, 36–46.
Fallon, P.G., Richardson, E.J., McKenzie, G.J., McKenzie, A.N., 2000. Schistosome
infection of transgenic mice defines distinct and contrasting pathogenic roles
for IL-4 and IL-13: IL-13 is a profibrotic agent. J. Immunol. 164, 2585–2591.
Feary, J., Britton, J., Leonardi-Bee, J., 2011. Atopy and current intestinal parasite
infection: a systematic review and meta-analysis. Allergy 66, 569–578.
Feary, J., Venn, A., Brown, A., Hooi, D., Falcone, F.H., Mortimer, K., Pritchard, D.I.,
Britton, J., 2009. Safety of hookworm infection in individuals with measurable
airway responsiveness: a randomized placebo-controlled feasibility study. Clin.
Exp. Allergy 39, 1060–1068.
Fleming, J.O., 2011. Helminths and multiple sclerosis: will old friends give us new
treatments for MS? J. Neuroimmunol. 233, 3–5.
Fleming, J.O., Isaak, A., Lee, J.E., Luzzio, C.C., Carrithers, M.D., Cook, T.D., Field, A.S.,
Boland, J., Fabry, Z., 2011. Probiotic helminth administration in relapsingremitting multiple sclerosis: a phase 1 study. Mult. Scler. 17, 743–754.
Gems, D., Ferguson, C.J., Robertson, B.D., Nieves, R., Page, A.P., Blaxter, M.L., Maizels,
R.M., 1995. An abundant, trans-spliced mRNA from Toxocara canis infective
larvae encodes a 26-kDa protein with homology to phosphatidylethanolaminebinding proteins. J. Biol. Chem. 270, 18517–18522.
Gordon, S., 2003. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–
35.
Grainger, J.R., Smith, K.A., Hewitson, J.P., McSorley, H.J., Harcus, Y., Filbey, K.J.,
Finney, C.A., Greenwood, E.J., Knox, D.P., Wilson, M.S., Belkaid, Y., Rudensky,
A.Y., Maizels, R.M., 2010. Helminth secretions induce de novo T cell Foxp3
expression and regulatory function through the TGF-beta pathway. J. Exp. Med.
207, 2331–2341.
Gregory, W.F., Maizels, R.M., 2008. Cystatins from filarial parasites: evolution,
adaptation and function in the host-parasite relationship. Int. J. Biochem. Cell
Biol. 40, 1389–1398.
Gruden-Movsesijan, A., Ilic, N., Colic, M., Majstorovic, I., Vasilev, S., Radovic, I.,
Sofronic-Milosavljevic, L., 2011. The impact of Trichinella spiralis excretorysecretory products on dendritic cells. Comp. Immunol. Microbiol. Infect. Dis. 34,
429–439.
Guasconi, L., Serradell, M.C., Masih, D.T., 2012. Fasciola hepatica products induce
apoptosis of peritoneal macrophages. Vet. Immunol. Immunopathol. 148, 359–
363.
Hall, J.A., Grainger, J.R., Spencer, S.P., Belkaid, Y., 2011. The role of retinoic acid in
tolerance and immunity. Immunity 35, 13–22.
Hamilton, C.M., Dowling, D.J., Loscher, C.E., Morphew, R.M., Brophy, P.M., O’Neill,
S.M., 2009. The Fasciola hepatica tegumental antigen suppresses dendritic cell
maturation and function. Infect. Immun. 77, 2488–2498.
Harn, D.A., McDonald, J., Atochina, O., Da’dara, A.A., 2009. Modulation of host
immune responses by helminth glycans. Immunol. Rev. 230, 247–257.
Harnett, W., Harnett, M.M., 2010. Helminth-derived immunomodulators: can
understanding the worm produce the pill? Nat. Rev. Immunol. 10, 278–284.
Hartmann, S., Lucius, R., 2003. Modulation of host immune responses by nematode
cystatins. Int. J. Parasitol. 33, 1291–1302.
Hawdon, J.M., Jones, B.F., Hoffman, D.R., Hotez, P.J., 1996. Cloning and
characterization of Ancylostoma-secreted protein. A novel protein associated
with the transition to parasitism by infective hookworm larvae. J. Biol. Chem.
271, 6672–6678.
He, Y., Barker, S.J., MacDonald, A.J., Yu, Y., Cao, L., Li, J., Parhar, R., Heck, S., Hartmann,
S., Golenbock, D.T., Jiang, S., Libri, N.A., Semper, A.E., Rosenberg, W.M.,
Lustigman, S., 2009. Recombinant Ov-ASP-1, a Th1-biased protein adjuvant
derived from the helminth Onchocerca volvulus, can directly bind and activate
antigen-presenting cells. J. Immunol. 182, 4005–4016.
Herbst, T., Esser, J., Prati, M., Kulagin, M., Stettler, R., Zaiss, M.M., Hewitson, J.P.,
Merky, P., Verbeek, J.S., Bourquin, C., Camberis, M., Prout, M., Maizels, R.M., Le
Gros, G., Harris, N.L., 2012. Antibodies and IL-3 support helminth-induced
basophil expansion. Proc. Natl. Acad. Sci. USA 109, 14954–14959.
Hewitson, J.P., Filbey, K.J., Grainger, J.R., Dowle, A.A., Pearson, M., Murray, J., Harcus,
Y., Maizels, R.M., 2011a. Heligmosomoides polygyrus elicits a dominant
nonprotective antibody response directed against restricted glycan and
peptide epitopes. J. Immunol. 187, 4764–4777.
Hewitson, J.P., Grainger, J.R., Maizels, R.M., 2009. Helminth immunoregulation: the
role of parasite secreted proteins in modulating host immunity. Mol. Biochem.
Parasitol. 167, 1–11.
Hewitson, J.P., Harcus, Y., Murray, J., van Agtmaal, M., Filbey, K.J., Grainger, J.R.,
Bridgett, S., Blaxter, M.L., Ashton, P.D., Ashford, D.A., Curwen, R.S., Wilson, R.A.,
Dowle, A.A., Maizels, R.M., 2011b. Proteomic analysis of secretory products from
the model gastrointestinal nematode Heligmosomoides polygyrus reveals
dominance of venom allergen-like (VAL) proteins. J. Proteomics 74,
1573–1594.
Hillwig, M.S., Rizhsky, L., Wang, Y., Umanskaya, A., Essner, J.J., MacIntosh, G.C., 2009.
Zebrafish RNase T2 genes and the evolution of secretory ribonucleases in
animals. BMC Evol. Biol. 9, 170.
Holland, M.J., Harcus, Y.M., Balic, A., Maizels, R.M., 2005. Th2 induction by
Nippostrongylus secreted antigens in mice deficient in B cells, eosinophils or
MHC Class I-related receptors. Immunol. Lett. 96, 93–101.
Holland, M.J., Harcus, Y.M., Riches, P.L., Maizels, R.M., 2000. Proteins secreted by the
parasitic nematode Nippostrongylus brasiliensis act as adjuvants for Th2
responses. Eur. J. Immunol. 30, 1977–1987.
Hubner, M.P., Stocker, J.T., Mitre, E., 2009. Inhibition of type 1 diabetes in filariainfected non-obese diabetic mice is associated with a T helper type 2 shift and
induction of FoxP3+ regulatory T cells. Immunology 127, 512–522.
Hunter, M.M., Wang, A., Parhar, K.S., Johnston, M.J., Van Rooijen, N., Beck, P.L.,
McKay, D.M., 2010. In vitro-derived alternatively activated macrophages reduce
colonic inflammation in mice. Gastroenterology 138, 1395–1405.
Idzko, M., Hammad, H., van Nimwegen, M., Kool, M., Willart, M.A., Muskens, F.,
Hoogsteden, H.C., Luttmann, W., Ferrari, D., Di Virgilio, F., Virchow Jr., J.C.,
Lambrecht, B.N., 2007. Extracellular ATP triggers and maintains asthmatic
airway inflammation by activating dendritic cells. Nat. Med. 13, 913–919.
Itami, D.M., Oshiro, T.M., Araujo, C.A., Perini, A., Martins, M.A., Macedo, M.S.,
Macedo-Soares, M.F., 2005. Modulation of murine experimental asthma by
Ascaris suum components. Clin. Exp. Allergy 35, 873–879.
Jang, S.W., Cho, M.K., Park, M.K., Kang, S.A., Na, B.K., Ahn, S.C., Kim, D.H., Yu, H.S.,
2011. Parasitic helminth cystatin inhibits DSS-induced intestinal inflammation
via IL-10(+)F4/80(+) macrophage recruitment. Korean J. Parasitol. 49, 245–254.
Jankovic, D., Kullberg, M.C., Caspar, P., Sher, A., 2004. Parasite-induced Th2
polarization is associated with down-regulated dendritic cell responsiveness
to Th1 stimuli and a transient delay in T lymphocyte cycling. J. Immunol. 173,
2419–2427.
Johnston, M.J., Wang, A., Catarino, M.E., Ball, L., Phan, V.C., MacDonald, J.A., McKay,
D.M., 2010. Extracts of the rat tapeworm, Hymenolepis diminuta, suppress
macrophage activation in vitro and alleviate chemically induced colitis in mice.
Infect. Immun. 78, 1364–1375.
Jouvin, M.H., Kinet, J.P., 2012. Trichuris suis ova: testing a helminth-based therapy as
an extension of the hygiene hypothesis. J. Allergy Clin. Immunol. 130, 3–10.
Kaur, I., Schramm, G., Everts, B., Scholzen, T., Kindle, K.B., Beetz, C., Montiel-Duarte,
C., Blindow, S., Jones, A.T., Haas, H., Stolnik, S., Heery, D.M., Falcone, F.H., 2011.
Interleukin-4-inducing principle from Schistosoma mansoni eggs contains a
functional C-terminal nuclear localization signal necessary for nuclear
H.J. McSorley et al. / International Journal for Parasitology 43 (2013) 301–310
translocation in mammalian cells but not for its uptake. Infect. Immun. 79,
1779–1788.
Kim, H.R., Lee, S.M., Won, J.W., Lim, W., Moon, B.I., Yang, H.J., Seoh, J.Y., 2012a.
Functional changes in regulatory T cells during an experimental infection with
sparganum (plerocercoid of Spirometra mansoni). Immunology 138, 57–67.
Kim, J.Y., Cho, M.K., Choi, S.H., Lee, K.H., Ahn, S.C., Kim, D.H., Yu, H.S., 2010. Inhibition
of dextran sulfate sodium (DSS)-induced intestinal inflammation via enhanced
IL-10 and TGF-beta production by galectin-9 homologues isolated from
intestinal parasites. Mol. Biochem. Parasitol. 174, 53–61.
Kim, S.H., Bae, Y.A., Yang, H.J., Shin, J.H., Diaz-Camacho, S.P., Nawa, Y., Kang, I., Kong,
Y., 2012b. Structural and binding properties of two paralogous fatty acid
binding proteins of Taenia solium metacestode. PLoS Negl. Trop. Dis. 6, e1868.
Koyasu, S., Moro, K., 2011. Innate Th2-type immune responses and the natural
helper cell, a newly identified lymphocyte population. Curr. Opin. Allergy Clin.
Immunol. 11, 109–114.
Kuijk, L.M., Klaver, E.J., Kooij, G., van der Pol, S.M., Heijnen, P., Bruijns, S.C., Kringel,
H., Pinelli, E., Kraal, G., de Vries, H.E., Dijkstra, C.D., Bouma, G., van Die, I., 2012.
Soluble helminth products suppress clinical signs in murine experimental
autoimmune encephalomyelitis and differentially modulate human dendritic
cell activation. Mol. Immunol. 51, 210–218.
Larson, D., Hubner, M.P., Torrero, M.N., Morris, C.P., Brankin, A., Swierczewski, B.E.,
Davies, S.J., Vonakis, B.M., Mitre, E., 2012. Chronic helminth infection reduces
basophil responsiveness in an IL-10-dependent manner. J. Immunol. 188, 4188–
4199.
Lee, K.H., Park, H.K., Jeong, H.J., Park, S.K., Lee, S.J., Choi, S.H., Cho, M.K., Ock, M.S.,
Hong, Y.C., Yu, H.S., 2008. Immunization of proteins from Toxascaris leonina
adult worm inhibits allergic specific Th2 response. Vet. Parasitol. 156, 216–225.
Lefrancais, E., Roga, S., Gautier, V., Gonzalez-de-Peredo, A., Monsarrat, B., Girard, J.P.,
Cayrol, C., 2012. IL-33 is processed into mature bioactive forms by neutrophil
elastase and cathepsin G. Proc. Natl. Acad. Sci. USA 109, 1673–1678.
Leonardi-Bee, J., Pritchard, D., Britton, J., 2006. Asthma and current intestinal
parasite infection: systematic review and meta-analysis. Am. J. Respir. Crit. Care
Med. 174, 514–523.
Lima, C., Perini, A., Garcia, M.L., Martins, M.A., Teixeira, M.M., Macedo, M.S., 2002.
Eosinophilic inflammation and airway hyper-responsiveness are profoundly
inhibited by a helminth (Ascaris suum) extract in a murine model of asthma.
Clin. Exp. Allergy 32, 1659–1666.
Liu, F.T., Yang, R.Y., Hsu, D.K., 2012. Galectins in acute and chronic inflammation.
Ann. N.Y. Acad. Sci. 1253, 80–91.
Maizels, R.M., Hewitson, J.P., 2012. Immune recognition of parasite glycans. In:
Kosma, P., Müller-Loennies, S. (Eds.), Anticarbohydrate Antibodies – From
Molecular Basis to Clinical Application. Springer, New York and Vienna, pp.
161–180.
Maizels, R.M., Hewitson, J.P., Murray, J., Harcus, Y.M., Dayer, B., Filbey, K.J., Grainger,
J.R., McSorley, H.J., Reynolds, L.A., Smith, K.A., 2012. Immune modulation and
modulators in Heligmosomoides polygyrus infection. Exp. Parasitol. 132, 76–89.
Mallevaey, T., Fontaine, J., Breuilh, L., Paget, C., Castro-Keller, A., Vendeville, C.,
Capron, M., Leite-de-Moraes, M., Trottein, F., Faveeuw, C., 2007. Invariant and
noninvariant natural killer T cells exert opposite regulatory functions on the
immune response during murine schistosomiasis. Infect. Immun. 75, 2171–
2180.
Manoury, B., Gregory, W.F., Maizels, R.M., Watts, C., 2001. Bm-CPI-2, a cystatin
homolog secreted by the filarial parasite Brugia malayi, inhibits class II MHCrestricted antigen processing. Curr. Biol. 11, 447–451.
Marsland, B.J., Camberis, M., Le Gros, G., 2005. Secretory products from infective
forms of Nippostrongylus brasiliensis induce a rapid allergic airway inflammatory
response. Immunol. Cell Biol. 83, 40–47.
Massacand, J.C., Stettler, R.C., Meier, R., Humphreys, N.E., Grencis, R.K., Marsland,
B.J., Harris, N.L., 2009. Helminth products bypass the need for TSLP in Th2
immune responses by directly modulating dendritic cell function. Proc. Natl.
Acad. Sci. USA 106, 13968–13973.
McCoy, K.D., Stoel, M., Stettler, R., Merky, P., Fink, K., Senn, B.M., Schaer, C.,
Massacand, J., Odermatt, B., Oettgen, H.C., Zinkernagel, R.M., Bos, N.A.,
Hengartner, H., Macpherson, A.J., Harris, N.L., 2008. Polyclonal and specific
antibodies mediate protective immunity against enteric helminth infection. Cell
Host Microbe 4, 362–373.
McSorley, H.J., Gaze, S., Daveson, J., Jones, D., Anderson, R.P., Clouston, A., Ruyssers,
N.E., Speare, R., McCarthy, J.S., Engwerda, C.R., Croese, J., Loukas, A., 2011.
Suppression of inflammatory immune responses in celiac disease by
experimental hookworm infection. PLoS One 6, e24092.
McSorley, H.J., Maizels, R.M., 2012. Helminth infections and host immune
regulation. Clin. Microbiol. Rev. 25, 585–608.
McSorley, H.J., O’Gorman, M.T., Blair, N., Sutherland, T.E., Filbey, K.J., Maizels, R.M.,
2012. Suppression of type 2 immunity and allergic airway inflammation by
secreted products of the helminth Heligmosomoides polygyrus. Eur. J. Immunol.
42, 2667–2682.
Molehin, A.J., Gobert, G.N., McManus, D.P., 2012. Serine protease inhibitors of
parasitic helminths. Parasitology 139, 681–695.
Molloy, M.J., Bouladoux, N., Belkaid, Y., 2012. Intestinal microbiota: shaping local
and systemic immune responses. Semin. Immunol. 24, 58–66.
Moser, M., Murphy, K.M., 2000. Dendritic cell regulation of TH1–TH2 development.
Nat. Immunol. 1, 199–205.
Motomura, Y., Wang, H., Deng, Y., El-Sharkawy, R.T., Verdu, E.F., Khan, W.I., 2009.
Helminth antigen-based strategy to ameliorate inflammation in an
experimental model of colitis. Clin. Exp. Immunol. 155, 88–95.
309
Mulvenna, J., Hamilton, B., Nagaraj, S.H., Smyth, D., Loukas, A., Gorman, J.J., 2009.
Proteomics analysis of the excretory/secretory component of the blood-feeding
stage of the hookworm, Ancylostoma caninum. Mol. Cell. Proteomics 8,
109–121.
Nisbet, A.J., Smith, S.K., Armstrong, S., Meikle, L.I., Wildblood, L.A., Beynon, R.J.,
Matthews, J.B., 2010. Teladorsagia circumcincta: activation-associated secreted
proteins in excretory/secretory products of fourth stage larvae are targets of
early IgA responses in infected sheep. Exp. Parasitol. 125, 329–337.
Nisbet, A.J., Zarlenga, D.S., Knox, D.P., Meikle, L.I., Wildblood, L.A., Matthews, J.B.,
2011. A calcium-activated apyrase from Teladorsagia circumcincta: an excretory/
secretory antigen capable of modulating host immune responses? Parasite
Immunol. 33, 236–243.
Nono, J.K., Pletinckx, K., Lutz, M.B., Brehm, K., 2012. Excretory/secretory-products of
Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in
dendritic cells in vitro. PLoS Negl. Trop. Dis. 6, e1516.
Ostanin, D.V., Bao, J., Koboziev, I., Gray, L., Robinson-Jackson, S.A., KosloskiDavidson, M., Price, V.H., Grisham, M.B., 2009. T cell transfer model of chronic
colitis: concepts, considerations, and tricks of the trade. Am. J. Physiol.
Gastrointest. Liver Physiol. 296, G135–146.
Panda, S.K., Kumar, S., Tupperwar, N.C., Vaidya, T., George, A., Rath, S., Bal, V.,
Ravindran, B., 2012. Chitohexaose activates macrophages by alternate pathway
through TLR4 and blocks endotoxemia. PLoS Pathog. 8, e1002717.
Pearce, E.J., MacDonald, A.S., 2002. The immunobiology of schistosomiasis. Nat. Rev.
Immunol. 2, 499–511.
Quinnell, R.J., 2003. Genetics of susceptibility to human helminth infection. Int. J.
Parasitol. 33, 1219–1231.
Rabinovich, G.A., Baum, L.G., Tinari, N., Paganelli, R., Natoli, C., Liu, F.T., Iacobelli, S.,
2002. Galectins and their ligands: amplifiers, silencers or tuners of the
inflammatory response? Trends Immunol. 23, 313–320.
Robinson, M.W., Alvarado, R., To, J., Hutchinson, A.T., Dowdell, S.N., Lund, M.,
Turnbull, L., Whitchurch, C.B., O’Brien, B.A., Dalton, J.P., Donnelly, S., 2012. A
helminth cathelicidin-like protein suppresses antigen processing and
presentation in macrophages via inhibition of lysosomal vATPase. FASEB J. 26,
4614–4627.
Robinson, M.W., Donnelly, S., Hutchinson, A.T., To, J., Taylor, N.L., Norton, R.S.,
Perugini, M.A., Dalton, J.P., 2011. A family of helminth molecules that modulate
innate cell responses via molecular mimicry of host antimicrobial peptides.
PLoS Pathog. 7, e1002042.
Ruyssers, N.E., De Winter, B.Y., De Man, J.G., Loukas, A., Pearson, M.S., Weinstock,
J.V., Van den Bossche, R.M., Martinet, W., Pelckmans, P.A., Moreels, T.G., 2009.
Therapeutic potential of helminth soluble proteins in TNBS-induced colitis in
mice. Inflamm. Bowel Dis. 15, 491–500.
Rzepecka, J., Siebeke, I., Coltherd, J.C., Kean, D.E., Steiger, C.N., Al-Riyami, L.,
McSharry, C., Harnett, M.M., Harnett, W., 2012. The helminth product, ES-62,
protects against airway inflammation by resetting the Th cell phenotype. Int. J.
Parasitol. (this issue).
Schenk, U., Frascoli, M., Proietti, M., Geffers, R., Traggiai, E., Buer, J., Ricordi, C.,
Westendorf, A.M., Grassi, F., 2011. ATP inhibits the generation and function of
regulatory T cells through the activation of purinergic P2X receptors. Sci. Signal.
4, ra12.
Schnoeller, C., Rausch, S., Pillai, S., Avagyan, A., Wittig, B.M., Loddenkemper, C.,
Hamann, A., Hamelmann, E., Lucius, R., Hartmann, S., 2008. A helminth
immunomodulator reduces allergic and inflammatory responses by induction
of IL-10-producing macrophages. J. Immunol. 180, 4265–4272.
Schramm, G., Mohrs, K., Wodrich, M., Doenhoff, M.J., Pearce, E.J., Haas, H., Mohrs, M.,
2007. Cutting edge: IPSE/alpha-1, a glycoprotein from Schistosoma mansoni
eggs, induces IgE-dependent, antigen-independent IL-4 production by murine
basophils in vivo. J. Immunol. 178, 6023–6027.
Segura, M., Su, Z., Piccirillo, C., Stevenson, M.M., 2007. Impairment of dendritic cell
function by excretory-secretory products: a potential mechanism for
nematode-induced immunosuppression. Eur. J. Immunol. 37, 1887–1904.
Semnani, R.T., Venugopal, P.G., Mahapatra, L., Skinner, J.A., Meylan, F., Chien, D.,
Dorward, D.W., Chaussabel, D., Siegel, R.M., Nutman, T.B., 2008. Induction of
TRAIL- and TNF-alpha-dependent apoptosis in human monocyte-derived
dendritic cells by microfilariae of Brugia malayi. J. Immunol. 181, 7081–7089.
Serradell, M.C., Guasconi, L., Cervi, L., Chiapello, L.S., Masih, D.T., 2007. Excretorysecretory products from Fasciola hepatica induce eosinophil apoptosis by a
caspase-dependent mechanism. Vet. Immunol. Immunopathol. 117, 197–208.
Smith, K.A., Harcus, Y., Garbi, N., Hammerling, G.J., Macdonald, A.S., Maizels, R.M.,
2012. Type 2 innate immunity in helminth infection is induced redundantly and
acts autonomously following CD11c+ cell depletion. Infect. Immun. 80, 3481–
3489.
Steinfelder, S., Andersen, J.F., Cannons, J.L., Feng, C.G., Joshi, M., Dwyer, D., Caspar, P.,
Schwartzberg, P.L., Sher, A., Jankovic, D., 2009. The major component in
schistosome eggs responsible for conditioning dendritic cells for Th2
polarization is a T2 ribonuclease (omega-1). J. Exp. Med. 206, 1681–1690.
Strachan, D.P., 1989. Hay fever, hygiene, and household size. BMJ 299, 1259–1260.
Summers, R.W., Elliott, D.E., Qadir, K., Urban Jr., J.F., Thompson, R., Weinstock, J.V.,
2003. Trichuris suis seems to be safe and possibly effective in the treatment of
inflammatory bowel disease. Am. J. Gastroenterol. 98, 2034–2041.
Summers, R.W., Elliott, D.E., Urban Jr., J.F., Thompson, R., Weinstock, J.V., 2005a.
Trichuris suis therapy in Crohn’s disease. Gut 54, 87–90.
Summers, R.W., Elliott, D.E., Urban Jr., J.F., Thompson, R.A., Weinstock, J.V., 2005b.
Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial.
Gastroenterology 128, 825–832.
310
H.J. McSorley et al. / International Journal for Parasitology 43 (2013) 301–310
Sutherland, T.E., Maizels, R.M., Allen, J.E., 2009. Chitinases and chitinase-like
proteins: potential therapeutic targets for the treatment of T-helper type 2
allergies. Clin. Exp. Allergy 39, 943–955.
Sutton, T.L., Zhao, A., Madden, K.B., Elfrey, J.E., Tuft, B.A., Sullivan, C.A., Urban Jr., J.F.,
Shea-Donohue, T., 2008. Anti-Inflammatory mechanisms of enteric
Heligmosomoides polygyrus infection against trinitrobenzene sulfonic acidinduced colitis in a murine model. Infect. Immun. 76, 4772–4782.
Terrazas, C.A., Sanchez-Munoz, F., Mejia-Dominguez, A.M., Amezcua-Guerra, L.M.,
Terrazas, L.I., Bojalil, R., Gomez-Garcia, L., 2011. Cestode antigens induce a
tolerogenic-like phenotype and inhibit LPS inflammatory responses in human
dendritic cells. Int. J. Biol. Sci. 7, 1391–1400.
Trujillo-Vargas, C.M., Werner-Klein, M., Wohlleben, G., Polte, T., Hansen, G., Ehlers,
S., Erb, K.J., 2007. Helminth-derived products inhibit the development of allergic
responses in mice. Am. J. Respir. Crit. Care Med. 175, 336–344.
Tudor, J.E., Pallaghy, P.K., Pennington, M.W., Norton, R.S., 1996. Solution structure of
ShK toxin, a novel potassium channel inhibitor from a sea anemone. Nat. Struct.
Biol. 3, 317–320.
Walk, S.T., Blum, A.M., Ewing, S.A., Weinstock, J.V., Young, V.B., 2010. Alteration of
the murine gut microbiota during infection with the parasitic helminth
Heligmosomoides polygyrus. Inflamm. Bowel Dis. 16, 1841–1849.
Wilson, M.S., Mentink-Kane, M.M., Pesce, J.T., Ramalingam, T.R., Thompson, R.,
Wynn, T.A., 2007. Immunopathology of schistosomiasis. Immunol. Cell Biol. 85,
148–154.
Wirtz, S., Neufert, C., Weigmann, B., Neurath, M.F., 2007. Chemically induced mouse
models of intestinal inflammation. Nat. Protoc. 2, 541–546.
Yamazaki, S., Inaba, K., Tarbell, K.V., Steinman, R.M., 2006. Dendritic cells expand
antigen-specific Foxp3+ CD25+ CD4+ regulatory T cells including suppressors of
alloreactivity. Immunol. Rev. 212, 314–329.
Yang, J., Zhao, J., Yang, Y., Zhang, L., Yang, X., Zhu, X., Ji, M., Sun, N., Su, C., 2007.
Schistosoma japonicum egg antigens stimulate CD4 CD25 T cells and modulate
airway inflammation in a murine model of asthma. Immunology 120,
8–18.
Yatsuda, A.P., Krijgsveld, J., Cornelissen, A.W., Heck, A.J., de Vries, E., 2003.
Comprehensive analysis of the secreted proteins of the parasite Haemonchus
contortus reveals extensive sequence variation and differential immune
recognition. J. Biol. Chem. 278, 16941–16951.
Young, N.D., Jex, A.R., Li, B., Liu, S., Yang, L., Xiong, Z., Li, Y., Cantacessi, C., Hall, R.S.,
Xu, X., Chen, F., Wu, X., Zerlotini, A., Oliveira, G., Hofmann, A., Zhang, G., Fang, X.,
Kang, Y., Campbell, B.E., Loukas, A., Ranganathan, S., Rollinson, D., Rinaldi, G.,
Brindley, P.J., Yang, H., Wang, J., Gasser, R.B., 2012. Whole-genome sequence of
Schistosoma haematobium. Nat. Genet. 44, 221–225.
Younis, A.E., Geisinger, F., Ajonina-Ekoti, I., Soblik, H., Steen, H., Mitreva, M.,
Erttmann, K.D., Perbandt, M., Liebau, E., Brattig, N.W., 2011. Stage-specific
excretory-secretory small heat shock proteins from the parasitic nematode
Strongyloides ratti–putative links to host’s intestinal mucosal defense system.
FEBS J. 278, 3319–3336.
Zaccone, P., Burton, O., Miller, N., Jones, F.M., Dunne, D.W., Cooke, A., 2009.
Schistosoma mansoni egg antigens induce Treg that participate in diabetes
prevention in NOD mice. Eur. J. Immunol. 39, 1098–1107.
Zaccone, P., Burton, O.T., Gibbs, S., Miller, N., Jones, F.M., Dunne, D.W., Cooke, A.,
2010. Immune modulation by Schistosoma mansoni antigens in NOD mice.
Effects on both innate and adaptive immune systems. J. Biomed. Biotechnol.
2010, 795210.
Zaccone, P., Burton, O.T., Gibbs, S.E., Miller, N., Jones, F.M., Schramm, G., Haas, H.,
Doenhoff, M.J., Dunne, D.W., Cooke, A., 2011. The S. mansoni glycoprotein
omega-1 induces Foxp3 expression in NOD mouse CD4(+) T cells. Eur. J.
Immunol. 41, 2709–2718.
Zaccone, P., Fehervari, Z., Jones, F.M., Sidobre, S., Kronenberg, M., Dunne, D.W.,
Cooke, A., 2003. Schistosoma mansoni antigens modulate the activity of the
innate immune response and prevent onset of type 1 diabetes. Eur. J. Immunol.
33, 1439–1449.
Zang, X., Maizels, R.M., 2001. Serine proteinase inhibitors from nematodes and the
arms race between host and pathogen. Trends Biochem. Sci. 26, 191–197.
Zang, X., Yazdanbakhsh, M., Jiang, H., Kanost, M.R., Maizels, R.M., 1999. A novel
serpin expressed by blood-borne microfilariae of the parasitic nematode Brugia
malayi inhibits human neutrophil serine proteinases. Blood 94, 1418–1428.
Zheng, X., Hu, X., Zhou, G., Lu, Z., Qiu, W., Bao, J., Dai, Y., 2008. Soluble egg antigen
from Schistosoma japonicum modulates the progression of chronic progressive
experimental autoimmune encephalomyelitis via Th2-shift response. J.
Neuroimmunol. 194, 107–114.
Zhou, Z.H., Chen, Y., Zhang, L., Wang, K., Guo, J., Huang, Z., Zhang, B., Huang, W., Jin,
K., Dou, T., Hasegawa, M., Wang, L., Zhang, Y., Zhou, J., Tao, L., Cao, Z., Li, Y., Vinar,
T., Brejova, B., Brown, D., Li, M., Miller, D.J., Blair, D., Zhong, Y., Chen, Z., Liu, F.,
Hu, W., Wang, Z.Q., Zhang, Q.H., Song, H.D., Chen, S., Xu, X., Xu, B., Ju, C., Huang,
Y., Brindley, P.J., McManus, D.P., Feng, Z., Han, Z.G., Lu, G., Ren, S., Wang, Y., Gu,
W., Kang, H., Chen, J., Chen, X., Chen, S., Wang, L., Yan, J., Wang, B., Lv, X., Jin, L.,
Wang, B., Pu, S., Zhang, X., Zhang, W., Hu, Q., Zhu, G., Wang, J., Yu, J., Wang, J.,
Yang, H., Ning, Z., Beriman, M., Wei, C.L., Ruan, Y., Zhao, G., Wang, S., Liu, F.,
Zhou, Y., Wang, Z.Q., Lu, G., Zheng, H., Brindley, P.J., McManus, D.P., Blair, D.,
Zhang, Q.H., Zhong, Y., Wang, S., Han, Z.G., Chen, Z., Wang, S., Han, Z.G., Chen, Z.,
2009. The Schistosoma japonicum genome reveals features of host-parasite
interplay. Nature 460, 345–351.