Article available at http://www.parasite-journal.org or http://dx.doi.org/10.

1051/parasite/2008153291

CURRENT TRENDS IN TISSUE-AFFECTING HELMINTHS

GOTTSTEIN B.* & PIARROUX R.**

Summary : lopment will primarily occur in the liver parenchyma.

Some helminths have by their evolution learnt to systemically Some other larval stages of cestodes (not Echinococcus),
invade a host organism, and to select specific organs or host cell and the newborn larval stage of the nematode Trichi-
types as predilection site to reside, maturate or even proliferate.
These parasites needed to develop complex and unique strategies
nella spiralis, will find their home in striated skeletal
to escape host immune reactions. The present work sheds some muscle tissue. Third stage larvae (Brunaska et al., 1995)
light into the strategy developed by three different helminths of Toxocara canis migrate to muscles, brain and visceral
(Echinococcus multilocularis, Trichinella spiralis and Toxocara tissues in human and other intermediate (paratenic)
canis) to survive in the host organ or host cell, respectively. The
crucial role of periparasitic host reactions that may help the host to
hosts. While Trichinella larvae have become successful
control the parasite, but which may also be responsible for as intracellular parasites, T. canis and E. multilocularis
immunopathological events harmful to the host himself, are principally remain at an extracellular stage of parasitism.
elucidated as well. Finally, for these three parasites selected, the All three parasite needed to develop complex and unique
murine host appears an acceptable model for carrying out
experimental studies, as for these parasites, rodents as well as
strategies to escape host immune reactions. Efficiency
humans become infected in the parasites natural life cycle. and efficacy of those strategies are proven by the fact
Therefore, conclusions drawn from murine experiments may that all three parasites are able to persist in their hosts
provide much more reliable data in view of their relevance for the for many years or more. They will survive in the organ
human infection, a fact that frequently lacks when using mice as
experimental model for other helminths.
or the host cell without actually causing death. There-
fore, these parasites are considered as very successful,
KEY WORDS : echinococcosis, trichinellosis, toxocariasis, immunity, in that disease is an aberrant finding occurring prima-
immunopathology, proteases.
rily only in humans, which do actually not participate
in the completion of the natural life cycle. In the follo-
wing chapter, we will shed some light into the parasite

T he list of helminthic parasites infecting humans is

long and rich in species diversity. Although the
most prominent fundamental niche parasitized by
these helminths is the gastro-intestinal (GI) tract, a series
of helminths have by their evolution learnt to systemi-
strategy developed to survive in the host organ or cell,
respectively, and into the periparasitic host reaction that
may help the host to control the parasite, but which may
also be responsible for immunopathological events
harmful to the host himself. Finally, for these three para-
cally invade the actual host organism, and to select spe- sites selected, the murine host appears an acceptable
cific organs or host cell types as predilection site to model for carrying out experimental studies, as for these
reside, maturate or even proliferate, until life-cycle conti- parasites, rodents as well as humans become infected
nues in another host. Some of these helminths enter the in the parasites natural life cycle. Therefore, conclusions
host via the GI, but subsequently they will continue their drawn from murine experiments may provide much
pathway by penetrating first into the intestinal epithe- more reliable data in view of their relevance for the
lium and lamina propria, after which they will be trans- human infection, a fact that frequently lacks when using
ported via blood or lymph to the anticipated predilec- mice as experimental model for other helminths.
tion site. Echinococcus multilocularis, after leaving the
intestinal tissue, will reach the next anatomical capillary
system represented by the liver, thus metacestode deve- BIOLOGICAL FEATURES OF ECHINOCOCCUS
* Institute of Parasitology, Vetsuisse Faculty, University of Bern, Bern, MULTILOCULARIS METACESTODES
Switzerland.

T
** Parasitology Department, SERF Team (quipe Sant Environnement he metacestode that causes alveolar echinococ-
Rural Franche-Comt), Faculty of Medicine, University of Franche-
cosis (AE) consists of a cluster of fluid-filled vesi-
Comt, Besanon, France.
Correspondence: Bruno Gottstein. cles, which are structured into a cellular and an
E-mail: [email protected] acellular compartment. The outer acellular surface of

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 GOTTSTEIN B. & PIARROUX R.

the metacestode is formed by the laminated layer, a

carbohydrate-rich structure synthesized by the parasite.
The laminated layer plays a crucial role in the survival
strategy of the parasite by modulating immunological
and physiological reactions on part of the host The
actual larval tissue is formed by the germinal layer, the
distal part of which consists of the tegument that is
directly associated with the inner surface of the lami-
nated layer. The tegument is characterized by micro-
villi-like extensions termed microtriches, which pro-
trude well into the matrix of the laminated layer and
increase the resorbing surface of the parasite. In addi-
tion, the germinal layer contains highly differentiated
cell types including connective tissue, muscle cells, and
glycogen storage cells, as well as many undifferentiated
cells. In E. multilocularis infection, metacestode deve-
lopment is closely intermingled with host (liver) connec-
tive tissue, the metacestode represents a multi-vesicular
structure that reproduces asexually, by exogenous for-
mation and budding of daughter vesicles, which resem- Fig. 1. Macroscopic cross-section through a primate liver heavly
affected by alveolar echinococcosis (metacestode of Echinococcus
bles progressive tumour-like growth (Fig. 1). This leads multilocularis).
to the formation of a large and heterogenuous para-
sitic mass, which exhibits mostly peripheral actively
proliferating sites, and in many cases, centrally located hampered by the fact, that the parasite synthesizes a
necrotic tissue. Metastases formation may occur in other carbohydrate-rich laminated layer in order to be pro-
organs due to release of germinal layer cells into the tected from host effector mechanisms (Gottstein &
blood or lymph system. E. multilocularis protoscoleces Hemphill, 1997). Another interesting feature observed
development in humans has been described only rarely. in chronic AE is a marked depression of the cell-media-
ted immune response (Baron & Tanner, 1976; Devouge
& Ali-Khan, 1983; Kizaki et al., 1991; 1993). These
general characteristics of E. multilocularis, including the
MURINE IMMUNE RESPONSE seemingly tumor like growth, its ability to modulate
IN E. MULTILOCULARIS INFECTION host immune responses, and the fact that in vitro cul-
ture is an established technique, renders this parasite

T he involvement of cellular immunity in control-

ling the infection is strongly suggested by the
intense granulomatous infiltration observed in
the periparasitic area of lesions in experimentally infec-
ted mice (Bresson-Hadni et al., 1990; Emery et al., 1996;
a very attractive model to study the host-parasite inter-
play in view to reveal potentially novel modes of the-
rapy (Vuitton, 2003). The larval infection with E. mul-
tilocularis begins with the intrahepatic postoncospheral
development of a metacestode. In certain cases, an
Vuitton et al., 1989). Immunodeficient athymic nude appropriate host immune response may inhibit para-
(Playford & Kamiya, 1992) and SCID mice (Playford et site proliferation. Several lines of evidence obtained in
al., 1992) as well as HIV-co-infected patients (Sailer et vivo and in vitro indicate the important bio-protective
al., 1997; Zingg et al., 2004) exhibited high suscepti- role of the LL (Gottstein et al., 2002). For instance, the
bility to infection and disease, thus suggesting that the LL has been proposed to protect the GL from nitric
host cell mediated immune response plays an impor- oxide produced by periparasitic macrophages and den-
tant role in suppressing the larval growth. E. multilo- dritic cells, and also to prevent immune recognition by
cularis appears to induce skewed Th2-responses surrounding T cells. On the other hand, the high per-
(Emery et al., 1996). Based on in vitro and in vivo stu- iparasitic NO production by peritoneal exudate cells
dies, Th2 dominated immunity was associated with contributes to periparasitic immunosuppression (Dai et
increased susceptibility to disease, while Th1 cell acti- al., 1999; Andrade et al., 2004), explaining why iNOS
vation through IL-12 (Emery et al., 1996), IFN (Liance deficient mice exhibit a significantly lower susceptibi-
et al., 1998; Jenne et al., 1998), TNF (Amiot et al., lity towards experimental infection (Dai et al., 2003).
1999) and IFN (Godot et al., 2003) was suggested to The intense periparasitic granulomatous infiltration
induce protective immunity in AE (Emery et al., 1998; indicates an intense host-parasite interaction, and the
Vuitton, 2003). Nevertheless, effective suppression of involvement of cellular immunity in control of the
larval growth by means of an immunological attack is metacestode growth kinetics is strongly suggested by

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292 Xth EMOP, August 2008
 TISSUE-AFFECTING HELMINTHS

experiments carried out in T cell deficient mouse strains of IL-10 by the PBMC seems to be the immunological
(Dai et al., 2004). Carbohydrate components of the LL, hallmark of patients with progressive forms of AE. IL-
such as Em2(G11) and Em492, as well as other para- 10-induced inhibition of effector macrophages but also
site metabolites yield immunomodulatory effects that of antigen-presenting dendritic cells may be operating
allow the parasite to survive in the host. I.e., the IgG to protect the parasitic growth and survival (Vuitton et
response to the Em2(G11)-antigen takes place inde- al., 2003). Susceptibility to infection in humans asso-
pendently of alpha-beta+CD4+ T cells, and in the ciates with predominantly TH2-related immunity (Wel-
absence of interactions between CD40 and CD40 ligand linghausen et al., 1999), including IL-10 (Godot et al.,
(Dai et al., 2001). Such parasite molecules also interfere 1997; 2000), IL-4 (Kilwinski et al., 1999), IL-5 (Sturm
with antigen presentation and cell activation, leading et al., 1995) production, especially during chronic stage
to a mixed Th1/Th2-type response at the later stage of infection.
of infection. Furthermore, Em492 (Walker et al., 2004)
as a purified parasite metabolite suppresses ConA and
antigen-stimulated splenocyte proliferation. Infected BIOLOGICAL FEATURES
mouse macrophages (AE-M) as APCs exhibited a redu-
ced ability to present a conventional antigen (chicken OF TRICHINELLA SPIRALIS
ovalbumin, C-Ova) to specific responder lymph node
T cells when compared to normal M (Mejri & Gott-
stein, 2006). As AE-M fully maintained their capacity
to appropriately process antigens, a failure in T cell
receptor occupancy by antigen-Ia complex or/and
A fter a newborn Trichinella larva enters its host
muscle cell, this larva will actively orchestrate
a series of architectural and constructional
modifications within the muscle cell that will finally
result in the formation of a nurse cell. This includes a
altered co-stimulatory signals can be excluded. Studying
the status of accessory molecules implicated in T cell dramatically altered portion of the infected myocyte,
stimulation by M, it could be shown that B7-1 (CD80)
and B7-2 (CD86) remained unchanged, whereas CD40
was down-regulated and CD54 (= ICAM-1) slightly up-
regulated. FACS analysis of peritoneal cells revealed a
decrease in the percentage of CD4+ and CD8+ T cells
in AE-infected mice. Taken together, the obstructed pre-
senting-activity of AE-M appeared to trigger an unres-
ponsiveness of T cells leading to the suppression of
their clonal expansion during the chronic phase of AE
infection (Mejri & Gottstein, 2006).

THE HUMAN IMMUNE RESPONSE

IN E. MULTILOCULARIS INFECTION

R elatively recent findings of naturally aborted

calcified liver lesions in patients from various
endemic areas (Godot et al., 2000; Gottstein et
al., 2001) have indicated that not all infected human
individuals allow the development of E. multilocularis
metacestode. Clinical research on such resistant cases,
but conversely also in AE patients with immunosup-
pression has disclosed some aspects of the survival
strategy of E. multilocularis in human hosts (Vuitton,
2003). Immunosuppressive status such as in liver trans-
plantation (Bresson-Hadni et al., 2003) or by AIDS
(Sailer et al., 1997; Zingg et al., 2004), especially when
suppressing cellular/Thl-related immunity, increases disease
severity (Harraga et al., 1999; Manfras et al., 2004). Most
studies so far have stressed a role for CD8+ T cells and
for Interleukin-10 in the development disease suscep- Fig. 2. Histological section through muscle tissue containing an
tibility (Vuitton et al., 1989). A spontaneous secretion encapsulated muscle stage larva of Trichinella spiralis.

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Xth EMOP, August 2008 293
 GOTTSTEIN B. & PIARROUX R.

devoid of muscle-specific proteins, which remains mul- maturating in its nurse cell, thew patient develops
tinucleated and whose predestinated functionis to sup- myalgia, fatique, elevated muscle enzymes and eosi-
port the growth, the maturation and the maintenance nophilia (Capo & Despommier, 1996). Eosinophilia is
of the parasite larva throughout the whole host life present in more than 90 % of the patients with symp-
(Despommier, 1998). The transformation of the original tomatic trichinellosis and abates only slowly over many
host muscle cell into a nurse cell takes approximately months. Pathogenetically, chronic inflammatory cells
15-20 days. The fully maturated and larve reside in a may surround the parasitized nurse cell. Vasculitis will
cyst encapsulated in an adventitious ellipsoidal sheath cause periorbital oedema as listed above, and neuro-
with blunt ends resulting from cellular reactions around logical manifestations as well as myocarditis are major
the tightly coiled larva (Fig. 2). Nourishing of the larva sequelae during trichinellosis of humans. Conversely
might be mainly via amino acids and carnohydrate to wild-life animal hosts, in man a calcification of the
metabolites so that it can remain alive for many years. cyst takes place after six months and may lead to death
The phenomenon of nurse cell transformation has of the larva.
been tackled experimentally, in view of determining
how the parasite modulates these events. Thus, the
addition of excretory/secretory (E/S) products from BIOLOGICAL FEATURES
newborn larvae or muscle larvae into a culture of myo-
cytes was shown to elicit morphological changes in OF TOXOCARA CANIS
myotubes, such as the formation of nodular structures
that contain numerous cavities, probably due to enzy-
matic digestion by parasitic proteases (Leung & Ko,
1997). Protease activities have been identified in (E/S)
products and crude extracts of T. spiralis (Criado-For-
T oxocariasis is a result of infection with embryo-
nated eggs from Toxocara canis or Toxocara cati.
After peroral ingestion of embryonated eggs by
an appropriate intermediate host including humans and
mice, the L3 (Brunaska et al., 1995) will hatch in the
nelio et al., 1992; de Armas-Serra et al., 1995; Todorova
et al., 1995; Todorova & Stoyanov, 2000; Todorova & small intestine, migrate to the intestinal wall and sub-
Stoyanov, 2000; Ros-Moreno et al., 2000). Serine pro- sequently circulate via the blood stream. After being
tease (Romaris et al., 2002; Nagano et al., 2003) and a blocked up in capillaries, larvae actively get through
metalloproteinase (Lun et al., 2003) were cloned and vascular wall and migrate into the host tissues (Fig. 3).
identified from E/S products of T. spiralis muscle larvae There, host cells gain contact with the larvae, and par-
(reviewed in Dzik, 2006; Trap et al., 2006). ticularly with their epicuticule, binding and releasing
large amount of Toxocara Excretory/Secretory (TES)
antigens. These antigens, first isolated by de Savigny
TRICHINELLA INFECTION IN THE HOST (1975), are produced by oesophageal glands and the
secretory apparatus of the larvae (Page et al., 1992a, b).

W hile there is ample information available on The metabolites are heavily glycosylated and they enti-
the dissection of the immune response against rely cover the surface of the larvae, thus representing
intestinal Trichinella infection, the respective the unique site of physical contact between parasite
information is much more scarce for the muscle stage and host (Page et al., 1992b). The results of this contact
infection. Some key components historically tackled as is a marked release of tumour necrosis factor alpha
being relevant to dictating the course of infection for (TNF-) and interleukine 8 (IL-8) which can specifically
muscle stage larvae of Trichinella spiralis include IgE, bind to receptors of endothelium cell of capillaries. Sti-
eosinophils and mast cells (Gurish et al., 2007; Wata- mulation of these cells results in an increase of expres-
nabe et al., 2005). More recently, some groups have sion of leukocyte adhesion molecule on their surface.
nicely addressed the cooperative interplay among IL- Neutrophils are the first cells to contribute to the inflam-
10 (Beiting et al., 2004), TGF-, Teff, and Treg that matory infiltrate into the lung of mice infected with
ensures parasite survival while protecting the host T. canis (Kayes, 2006). This early inflammatory infiltrate
from inflammatory disease in murine trichinellosis (Bei- represents the innate response, and is subsequently fol-
ting et al., 2007). Trichinellosis in humans is acquired lowed, after less than a week, by the binding of eosi-
by consuming the meat of host animals that contain nophils to endothelium cells receptors VCAM-1 and
viable encysted larvae of Trichinella spp. The muscle ELAM-1 (vascular cell adhesion molecule 1 and endo-
phase of the disease begins about one week after infec- thelial leucocyte adhesion molecule 1, respectively). A
tion when the larvae from the intestine disseminate Th2 response is considered as being responsible for
hematogenously and begin to encyst in striated mus- the hypereosinophilia and the IgE hyperglobulinemia.
cles. Patients may subsequently suffer from subconjunc- However, eosinophils, even with the cooperation of
tival, retinal and subungual splinter hemorrhages, and antibodies, are unable to kill infectious larvae. This is
periorbital and facial oedema. In line with the larvae partially due to the fact that larvae permanently slough

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294 Xth EMOP, August 2008
 TISSUE-AFFECTING HELMINTHS

human and mouse is characterized by high and per-

sisting eosinophilia, and production of cytokines typical
for a Th-2 type immune response (IL-4, IL-5, IL-10) and
increased IgE antibodies levels (Kayes, 1997) unable
to kill the larvae. Consequently, larvae can remain for
years in the muscle and brain and thus can cause long-
term chronic infection and disease.

TOXOCARA INFECTION IN THE HUMAN

HOST

I n humans, Toxocara typically causes two severe syn-

dromes called either visceral larva migrans (VLM)
or ocular larva migrans (OLM). OLM was first des-
cribed by Wilder (1950) who reported 24 cases in chil-
dren suspected of having retinoblastoma. Migration of
T. canis infectious stage larvae to the eye causes loss
of vision and the presence of only one larva in the
ocular cavity can cause irreversible blindness. VLM was
described two years later, by Beaver et al. (1952) in
three children suffering from hepatomegaly and hyper-
eosinophilia. VLM typically affects children with a his-
tory of geophagia and exposure to puppies at home.
In VLM cases, hepatic and pulmonary larval migration
induces clinical symptoms such as abdominal pain,
decreased appetite, restlessness, fever, coughing, whee-
zing, asthma and hepatomegaly. Cutaneous manifes-
tations includes transient rash, urticaria and hypoder-
mic nodules. The main laboratory findings are marked
Fig. 3. Histological presentation (HE-stain) of lung tissue contai-
ning three cross-sections of larvae from Toxocara canis, and many
eosinophilia, leukocytosis, hypergammaglobulinemia,
inflammatory cell infiltrates. anemia and hypoalbuminemia (Markell et al., 1999).
Less severe forms of toxocariasis occur in industrialized
countries and are called common toxocariasis and covert
off their epicuticule leading to an elimination of anti- toxocariasis. Common toxocariasis was first described
bodies and cells which are attacking the larva (Badley by Glickman et al. (1987) in French adults presenting
et al., 1987; Parson et al., 1993; Jones et al., 1994; Dent with weakness, breathing difficulties, abdominal pain,
et al., 1997, 1999; Ovington & Behm, 1997; Takamoto and also skin symptoms such as pruritus and rash asso-
et al., 1997). The migration of the larvae may also play ciated with biological signs of allergic manifestation
a role by helping the parasite to escape encapsulation (hypereosinophilia and increased total serum IgE). The
into granuloma. Finally, the role of eosinophils in the spectrum of covert toxocariasis was identified the same
resistance to Toxocara infection appears relatively year in Irish children (Taylor et al., 1987). It includes
minor (Dent et al., 1999; Meeusen & Balic, 2000) and various symptoms such as fever, anorexia, headache,
Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) abdominal pain, nausea, coughing, wheezing and beha-
directed against the incoming larvae in non-sensitized viour disorders.
hosts is hardly protective. Other cells may play a role,
such as the macrophages termed alternatively macro-
phages (Stein et al., 1992). These cells express F4/80, CONCLUSIONS
a macrophage surface marker molecule, and Nair et al.
(2003) showed that 10 % of the mRNAs isolated from
F4/80-positive cells encoded the YM-1 protein, a
member of the kitinase 18 family. These chitinases have
been reported in mice and in human and have been
implicated in helminth infection and in asthma and
I nnate and acquired immunity plays a central role in
recognizing and controlling the spread and impact
on the host of infectious organisms. In the case of
helminthic infections this task is significantly complica-
ted by the fact that many eukaryotic parasites have evol-
allergy. Finally, immune response against T. canis in ved sophisticated mechansims for evading the immune

Parasite, 2008, 15, 291-298

Xth EMOP, August 2008 295
 GOTTSTEIN B. & PIARROUX R.

response. Consequently, many diseases caused by hel- coccus multilocularis infection. II. Sequential and compa-
minths are chronic in nature and result in prolonged rative phenotypic study of the periparasitic mononuclear
and excessive immune responsiveness which in itself cells in resistant and sensitive mice. Clin. Exp. Immunol.,
can be deleterious. The study of immune responses to 1990, 82, 378-383.
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