Tissue migration by parasitic helminths– an immunoevasive strategy?Grace Mulcahy1, Sandra O’Neill2, June Fanning1, Elaine McCarthy1 and Mary Sekiya1

1Department of Veterinary Microbiology and Parasitology, Faculty of Veterinary Medicine and Conway Institute,

University College Dublin, Belfield, Dublin 4, Ireland2School of Nursing, Dublin City University, Dublin 9, Ireland

Migration through host tissues has major costs for

parasitic helminths in terms of energy expenditure, risks

of attrition and the need to adapt to varying physico-

chemical environments. Nevertheless, such migratory

phases seem to confer a specific survival advantage. One

reason for this might be the avoidance of specific host

immune-defence mechanisms designed to protect

against threats at mucosal surfaces.

Survival advantage of tissue migration by parasitic

helminths

An analysis by Read and Skorping of tissue migration byparasitic nematodes [1] concluded that, despite theobvious costs in terms of energy expenditure, adaptationto different physicochemical environments and increasedattrition, such migration conferred a specific survivalbenefit. They based their conclusion on a comparison ofrelated taxa with and without migratory phases andshowed that tissue migration was associated with greaterbody size and/or more-rapid maturation. The survivaladvantage could be an immune-evasion mechanism thatarose because of the evolution of T helper (Th)2 responsesfrom innate defence mechanisms specifically to deal withthreats at mucosal surfaces.

Th2 induction by parasitic helminths

The propensity of helminth parasites to induce polarizedTh2 responses is axiomatic in parasite immunology andwas instrumental in helping to formulate the Th1–Th2hypothesis. However, data about the mechanisms govern-ing Th2 induction are lacking compared with those forinduction of Th1 responses, particularly by bacteria [2]. Inboth cases, recognition of pathogen-associated molecularpatterns (PAMPS) by toll-like receptors (TLRs) isinvolved, with candidate helminth PAMPS includingglycans and lipid molecules [3–5]. Activation of TLR-4,through STAT-6 signalling, and the consequent alterna-tive activation of dendritic cells are now also considered tobe steps on the pathway to Th2 activation [6]. Recentevidence also suggests that dendritic cells process hel-minth and bacterial antigens in distinct intracellularcompartments [7]. The response to helminth infection inhigher animals has consistent features; however, theoutcome varies across a wide spectrum that ranges from

Corresponding author: Mulcahy, G. (grace.mulcahy@ucd.ie).Available online 20 April 2005

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chronic infection with little pathology, through slowacquisition of immunity, to an acute type-1 hypersensitivityreaction with parasite expulsion accompanied by markedimmunopathology.

Protective and regulatory Th2 responses

The clearance of or the protection against mucosalhelminth infections by Th2 effector mechanisms is evidentin several important model systems and in clinicallyimportant infections in humans and animals. Forexample, such responses deliver protection against hook-worm infection in humans [8], Ostertagia infection incattle [9] and intestinal Trichinella spiralis infection inmice [10,11]. The association of Th2 responses withhypersensitivity states and altered physiological function(eosinophilia, mastocytosis, increased numbers of gobletcells, altered mucin production and increased smooth-muscle contractility) makes it easy to see how theseresponses can lead to helminth expulsion from mucosae.However, the exact mechanisms vary for differenthelminths and are understood only partially. In thegastrointestinal tract, elimination sometimes involves a‘self-cure’ reaction and sudden elimination after a periodof infection. However, there are also many examples ofhelminths such as Heligmosomoides polygyrus in mice[12] and adult tapeworms in humans and dogs establish-ing chronic infections at mucosal sites at which self-curedoes not take place. Also, in the respiratory tract, elimina-tion and protective immunity can result from Th2responses, although this carries risks of immunopathology[13] because lung tissue is extremely sensitive to inflam-matory mediators. As with the gastrointestinal tract,there are examples of helminths living in the airways(such as Dictyocaulus spp. of deer and donkeys) that aretolerated well with little inflammatory reaction [14,15].

The phenomenon of chronic helminth infection hasrecently been linked to the co-induction of immuno-regulatory circuits by Th2-inducing parasitic helminths[16,17]. This might result in modulation of Th2 responsesand dampening of potentially damaging atopic or allergicresponses, but also downregulation of immune respon-siveness to other pathogens [18]. Induction of T-helperPAMPs stimulated by helminths at mucosal surfaces isalso implicated in recruitment and activation of regu-latory cell subsets such as CD4CCD25C, Th3 and Tregulatory (Tr)1 [17,19]. In addition, gd T cells, associated

Opinion TRENDS in Parasitology Vol.21 No.6 June 2005

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with mucosae, are involved in damping down potentiallypathogenic inflammatory and immunological reactions[20]. Although the molecular triggers or PAMPs respon-sible for Th2 responses are not as well defined as thoserecognized as being important in driving Th1 responses,potential candidates include lipid molecules and parasite-secreted enzymes. These downregulatory mechanismshave important consequences: for example, the inductionof tolerance to the vast majority of antigens encounteredafter ingestion or inhalation, and the induction oftolerance to paternal alloantigens during pregnancy [21].

One possible model to explain the persistence ofmucosal helminths in some situations and their elimin-ation in others supposes that tolerance is the ‘default’situation at mucosal surfaces, which is overcome onlywhen the stimulus towards Th2 effector mechanismsexceeds that towards regulatory mechanisms. Thus, forhelminths, there might be a threshold in terms of parasitedensity or numbers that determines the outcome –tolerance and regulation, or Th2-driven effector mechan-isms and expulsion. In feral animals, for example, guthelminth burdens remain within the tolerance threshold,essentially as part of the normal gut flora [22], until anartificial situation such as increased infection pressure ina farming scenario supervenes. Furthermore, helminthsin the gastrointestinal tract might protect against inflam-matory diseases [23].

Th2- versus Th1-mediated protection: a function of site

specificity?

A review of the literature about Th2-mediated protectionagainst helminth infection indicates that it has beencharacterized principally for helminths at mucosal sites(Table 1). Conversely, there are many examples oftissue-dwelling helminths that persist despite intenseTh2-mediated responses (Table 2). When migration is afeature of the helminth life cycle, Th2-dominated immun-ity is often much more effective against mucosal-dwelling

Table 1. Evidence of Th2-mediated protection against helminths a

Parasite Immune response or polarization P

Heligmsomoides

polygyrus

Th2 cytokines and antibody isotypes P

Ascaris lumbricoides Th2 cytokines produced by antigen-

stimulated lymphocytes in vitro

T

in

Trichinella spiralis

(intestinal stages)

Th2, with IL-10 regulating intestinal

mast-cell responses

T

in

la

Nippostrongylus

brasiliensis

Eosinophil infiltration; Stat-6 signalling

Necator americanus

(hookworm)

Th2 cytokines M

Trichuris muris Polarized Th2 cytokine environment

induced by infection

IL

Nematodirus battus Th2 cytokine profile R

Strongyloides papillosus Administration or IFN-g inhibits

Th2-mediated protection in calves

D

Ostertagia ostertagi Increased infiltration of lymphocytes,

eosinophils and mast cells; increased

smooth-muscle activity

S

Toxocara canis E

laaCommon pathogenic helminths of humans or domestic animals, and those importan

induction of polarized Th2 responses that are, at least partially, effective at mediating cbAbbreviations: IL, interleukin; KO, knockout.

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stages than against migratory stages. For example, adultworms of the ascarid Toxocara canis are eliminated fromthe small intestine of dogs by a combination of innate andadaptive immune responses. Larval stages, however, cansurvive for years in tissues [24]. Likewise, larvae of themigratory nematode Strongylus vulgaris in horses are noteliminated from their temporary resting site in the cranialmesenteric artery, although adult parasites are partiallycontrolled by immune-mediated mechanisms in the largeintestine. In most cases, the protective capacity of immuneresponses against mucosal-dwelling helminths is greaterthan that against stages dwelling in tissue spaces. Whenimmune responses are effective at eliminating tissuestages, there is abundant evidence that this can beorchestrated by the Th1 arm of the immune system(Table 2).

In addition, examples from vaccine studies show that,in some cases, it is possible to achieve protection againsttissue helminths by inducing Th1 responses (Table 2). Oneof the most striking examples of this is the use ofonchosphere antigens to vaccinate against larval tape-worms. Such vaccines against Taenia ovis in sheep, forexample, can induce almost 100% protection againstchallenge, with protection mediated by Th1 responses[25]. Infection with Fasciola hepatica, in both laboratoryanimals and ruminants, is such a potent inducer of Th2responses that ability to mount effective Th1 responsesagainst bacterial and other pathogens is impaired [17].Such responses are not protective in terms of eliminatingexisting infection or preventing new challenge [26].However, vaccination with F. hepatica cathepsin-L pro-teases in appropriate adjuvants can induce less-polarizedresponses (non-Th2 phenotype) and provide substantialprotection against challenge [27].

Tissue migration as immunoevasion?

The elaborate migratory pathways of many helminthparasites have a high cost in terms of energy expenditure,

t mucosal sitesa,b

rotective capacity Refs

rotective against trickle infection in SWA and CBA mice [34]

h2 response correlates inversely with intensity of infection in

dividuals over 11 years of age

[35]

h2 protective against intestinal stages only; IL-10 KOs have

creased IFN-g production and increased immunity to tissue

rval stages

[36]

[37]

ice can be protected by vaccine-induced Th2 response [8,38]

-10-deficient mice cannot resist infection [39]

apid self-cure [40]

evelopment of efficient protection [41]

low acquisition of immunity [42]

limination of intestinal stages; persistence of tissue-dwelling

rval stages

[24]

t in murine models of helminthosis are listed. In each case, there is evidence of

learance of infection and/or preventing reinfection.

Table 2. Evidence of protective mechanisms against tissue-dwelling helminthsa

Parasite Immune response Protective capacity Refs

Taenia spp.

(larval stages)

Th2 responses ineffective against tissue larval stages Th1-mediated protection can be induced by

vaccination with onchosphere antigens

[25,43]

Onchocerca volvulus Mixed Th1–Th2 responses Both Th1 and Th2 protective responses described [44,45]

Fasciola hepatica Polarized Th2 responses induced by infection Magnitude of infection-induced response

(nonprotective) correlates directly with parasite

burden; protective immune responses induced by

vaccination correlate inversely with parasite burden

[26,27]

Trichinella spiralis

(tissue stages)

Th2, with IL-10 regulating intestinal mast-cell

responses and promoting expulsion of intestinal

stages

Th2 protective against intestinal stages only;

abrogation of Th2 increases immunity to larval

stages in tissues; IL-10 KOs have increased IFN-g

production and increased immunity to tissue larval

stages

[10]

Schistosoma spp. Th2 responses against egg antigens do not lead to

expulsion of tissue-dwelling parasites; CpG

oligonucleotides can protect against Th2-mediated

pathology; Th1 or mixed responses can mediate

protection following vaccination

IL-10 is a risk factor for reinfection; protection by

rSM23 vaccination is mediated by Th1 responses

[46–49]

Toxocara canis

(tissue stages)

Th2 responses to both adult and larval antigens Persistence of latent larval stages for the lifetime

of the host; reactivation of larval stages in the

Th2-dominated environment of pregnancy

[24]

aEach helminth listed spends at least part of its life cycle migrating through host tissues. The species listed have all been studied intensively, either because of their

pathogenic importance or because of their usefulness as models for understanding helminth immunology. Overall, the balance of evidence points towards Th1-related

mechanisms being effective against these parasites, despite the fact that, like the helminths listed in Table 1, they tend to provoke polarized Th2 responses following

infection.

TRENDS in Parasitology

DC2DCr Th2Tr

Type-1 hypersensitivityMucosal helminth expulsionImmunopathology

Tolerance to mucosal stimuliPermissiveness to tissue antigensChronic helminth infection

Helminth PAMPs(glycans, lipids, enzymes, undefined molecules)

Arthropod PAMPs

Immature dendritic cells

Figure 1. Th2 and regulatory subsets induced by helminths. Because arthropods

induce similarly polarized responses, comparable interactions might occur during

host interaction with this group of macroparasites. The clearance or persistence of

helminths at mucosal surfaces might depend on the balance between effector and

regulatory mechanisms. Regulatory mechanisms are likely to prevail in tissue

spaces rather than at mucosal surfaces. Th2 mechanisms could have evolved from

innate immune defencemechanisms designed specifically to deal with threats from

macroparasites at mucosal surfaces. A Th2 environment promotes tolerance to

paternal alloantigens during pregnancy and to tissue grafts. Helminths might use

tissue migration as an immunoevasive strategy.

Opinion TRENDS in Parasitology Vol.21 No.6 June 2005 275

increased time to patency and losses before patency. Why,then, do so many helminth species migrate within the hostwhen this is not necessary to ensure that eggs can bepassed in faeces? One possible explanation is thatmigratory phases, even in the many species that bothgain access to the host and mature in the gastrointestinaltract, are a remnant of earlier life cycles in whichalternative routes of infection were used. However, thisdoes not account for the clear survival advantage providedby tissue migration when related migratory and non-migratory taxa are compared [1]. In some cases, thesurvival advantage of tissue migration is particularlydifficult to understand. The nematode S. vulgaris, forexample, infects horses by oral route and grows toreproductive maturity in the large intestine. Betweeningestion and maturity, however, the larval wormsmigrate, against the direction of blood flow, through thearterial system until they enter a resting phase, of up tosix months, in the lumen of the cranial mesenteric arterybefore returning to the large intestine [28]. OtherStrongylus spp. have a tissue-migratory phase thatinvolves connective tissue. There are also several notableexamples of helminths that use long-lived tissue larvalstages for transmission to new hosts, in conjunction withadults that have short life spans in the gastrointestinaltract. T. spiralis adults are susceptible to elimination fromthe gastrointestinal tract by classic Th2 responses [10],whereas the larvae, which migrate to muscles immedi-ately after production by adult females, can persistindefinitely in skeletal-muscle cells. Similarly, T. canisadults persist for only weeks in the small intestine of dogs,whereas arrested larvae can remain viable in tissuesindefinitely [24].

Is the migratory phase, therefore, useful to the wormsfor avoiding the effector consequences of Th2 responses(e.g. diarrhoea and increased smooth-muscle contractility)while the growth and development that are necessary foregg production occur? We propose that evasion of Th2

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responses that are suited to protecting against parasitesat mucosal surfaces is one such advantage provided bytissue migration in the life cycles of parasitic helminths.Studies to test this hypothesis in various animal modelsare warranted. In line with current thinking about inter-actions between Th2 responses and immunoregulatorycircuits, mechanisms governing the elimination and per-sistence of helminths in tissues and at mucosae arepresented in Figure 1.

Opinion TRENDS in Parasitology Vol.21 No.6 June 2005276

Implications for vaccine development

Despite intensive research efforts, progress in the develop-ment of effective anti-helminth vaccines has been rela-tively slow. Advances in biotechnology that facilitateproduction of antigens by recombinant technology promiseto overcome some of the associated difficulties. Whereasthe search for protective antigens has, correctly, occupiedcentre stage, the induction of appropriate responsesthrough use of specific vaccine administration routesand adjuvants has, perhaps, received less attention thanit deserves. Although there have been excellent funda-mental studies of the effect of adjuvants [29] and the routeof immunization [30] on response to helminth vaccines,they are vastly outnumbered by investigations about thesearch for protective antigens. One of the factors influenc-ing choice of adjuvant and vaccine formulation might bethe location of the parasite stage to be targeted. Rationalvaccine design for helminth infections must encompassselection of adjuvant and route of administration,informed by knowledge of protective mechanisms andimmunoevasion strategies such as those discussed in thisarticle. We suggest that the site of the target (i.e. atmucosal surfaces, in tissues or both) should be animportant consideration in this aspect of vaccine design.This paradigm could be relevant to vaccine design forother classes of pathogen. For example, Toxoplasmagondii, like other apicomplexans, is considered to besusceptible to Th1-mediated responses and, in particular,interferon (IFN)-g. However, a recent report shows thatprotection against the intestinal stages of this organismcan be mediated by Th2 responses [31].

Wider implications

Arthropods, like parasitic helminths, typically drive Th2responses, although little is known about the mechanismsgoverning Th2 induction by these parasites. However, itseems logical to assume that these polarized responsesevolved from innate immune mechanisms designed toprotect against threats at body surfaces (skin andmucosae) while, at the same time, preventing overreactionto commonly encountered, non-threatening alloantigens.Dysregulation of this immunoregulatory–effector balancemight be responsible for many cases of allergic andinflammatory diseases. Blood-feeding arthropods functionas vectors for many important and widespread protozoan,viral and bacterial pathogens, and Th2 polarizationinduced by arthropod vectors might be exploited by suchpathogens as an immunoevasive strategy [32].

Recognition of a distinction betweenmucosal and tissuesites in terms of the effectiveness of Th1 and Th2responses might, together with increased recognition ofthe importance of regulatory-T-cell subsets, prompt a re-evaluation of the distinct and complementary roles ofthese responses. The concept of Th1 subsets mediatingprotection against intracellular pathogens, and Th2responses mediating protection against extracellularpathogens is still a common topic of publication. Thisholds true in many situations; however, there are alsoexamples, including those discussed in this article,suggesting that the site of infection with extracellularparasites is also an important criterion in determining the

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nature of protective immune responses. This also seems tohave currency for immune responses other than thoseinduced by infection. During pregnancy, for example, Th2responses, in association with regulatory mechanisms,prevent foetal rejection, whereas Th1 responses can resultin immune-mediated pregnancy loss [21]. Similarly, acutegraft rejection is mediated by Th1 responses and isprevented by a Th2 environment [33]. The similaritybetween these situations and the persistence of tissue-dwelling helminths in a Th2-driven environment seemsclear.

Concluding remarks

The preferential induction of Th2 responses and associ-ated effector mechanisms (type-1 hypersensitivity) byparasitic helminths and arthropods has been clear formany years, although the interaction among PAMPs,TLRs, and innate and adaptive immune mechanismsinvolved in such polarized responses is only just beginningto be understood. An examination of the evidence of theprotective capacity of such responses in some situationsand the persistence of parasites in others leads to theconclusion that the site of immune reaction might be animportant component in determining protection or per-sistence. The responses generated by helminth infectionseem best suited to dealing with threats at mucosalsurfaces. A logical corollary is that helminths mighthave developed elaborate tissue-migratory pathways asimmunoevasive strategies. These concepts are relevant tothe design of vaccines for controlling parasitic helminthsand other pathogens, in addition to the understanding ofpolarization and regulation of immune responses.

At mucosal surfaces, induction of tolerance to dietaryand other environmental antigens is required and mightbe considered to be the default situation mediated byregulatory circuits associated with Th2 responses.Whether helminth infections at mucosal surfaces aretolerated or eliminated (sometimes, with accompanyingimmunopathology) might depend on the balance betweenregulatory and effector circuits, and the evolution inhelminths of mechanisms for minimizing the recognitionof PAMPs. Whereas some helminths have succeeded indoing this and, hence, establishing chronic infections,others might have adopted migration into tissue spaces asan alternative strategy for prolonging survival within thehost. In tissues, except in specific circumstances such asduring pregnancy, foreign antigens require elimination,with Th1 responses being the default state. Experimentsto test these hypotheses will be important for the design ofimmunoprophylaxis and immunotherapies in areas thatinclude, but are not confined to, parasite immunology.

Acknowledgements

We thank colleagues for constructive criticism of the manuscript. Owingto space restrictions, we have not cited all of the relevant original articlesand, instead, have cited appropriate recent reviews. Work in ourlaboratories is supported by Enterprise Ireland, the Health ResearchBoard, Irish Council for Science, Engineering and Technology, andTeagasc.

Opinion TRENDS in Parasitology Vol.21 No.6 June 2005 277

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