Toxocara canis: Molecular basis of immune recognition and evasion

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  • Veterinary Parasitology 193 (2013) 365 374

    Contents lists available at SciVerse ScienceDirect

    Veterinary Parasitology

    jo u rn al hom epa ge : www.elsev ier .com/ locate /vetpar

    Toxoca e re

    Rick M. MInstitute of Imm ories, W

    a r t i c l e i n f o

    Keywords:AntibodiesDiagnosisLarva migransMucinsSurface coat

    a b s t r a c t

    Toxocara canis has extraordinary abilities to survive for many years in the tissues of diversevertebrate species, as well as to develop to maturity in the intestinal tract of its deni-

    1. Introdu

    Toxocaraworm of dopotential fotoxocariasis

    Tel.: +44 1E-mail add

    0304-4017/$ http://dx.doi.otive canid host. Human disease is caused by larval stages invading musculature, brain andthe eye, and immune mechanisms appear to be ineffective at eliminating the infection.Survival of T. canis larvae can be attributed to two molecular strategies evolved by the par-asite. Firstly, it releases quantities of excretorysecretory products which include lectins,mucins and enzymes that interact with and modulate host immunity. For example, onelectin (CTL-1) is very similar to mammalian lectins, required for tissue inammation, sug-gesting that T. canis may interfere with leucocyte extravasation into infected sites. Thesecond strategy is the elaboration of a specialised mucin-rich surface coat; this is looselyattached to the parasite epicuticle in a fashion that permits rapid escape when host antibod-ies and cells adhere, resulting in an inammatory reaction around a newly vacated focus.The mucins have been characterised as bearing multiple glycan side-chains, consisting ofa blood-group-like trisaccharide with one or two O-methylation modications. Both thelectins and these trisaccharides are targeted by host antibodies, with anti-lectin antibodiesshowing particular diagnostic promise. Antibodies to the mono-methylated trisaccharideappear to be T. canis-specic, as this epitope is not found in the closely related Toxocara cati,but all other antigenic determinants are very similar between the two species. This distinc-tion may be important in designing new and more accurate diagnostic tests. Further toolsto control toxocariasis could also arise from understanding the molecular cues and stepsinvolved in larval development. In vitro-cultivated larvae express high levels of four mRNAsthat are translationally silenced, as the proteins they encode are not detectable in culturedlarvae. However, these appear to be produced once the parasite has entered the mam-malian host, as they are recognised by specic antibodies in infected patients. Elucidatingthe function of these genes, or analysing if micro-RNA translational silencing suppressesproduction of the proteins, may point towards new drug targets for tissue-phase parasitesin humans.

    2013 Elsevier B.V. All rights reserved.


    canis is the most prevalent intestinal round-gs, foxes and other canid species, with zoonoticr human beings. In many temperate countries,

    is the most common helminth infection and

    31 650 5511; fax: +44 131 650 5450.ress:

    causes a signicant morbidity (Despommier, 2003; Hotezand Wilkins, 2009; Rubinsky-Elefant et al., 2010; Smithet al., 2009).

    The nematode has many salient biological features,which contribute to its continuing presence in animaland human populations. Firstly, it is able to invade anextraordinarily wide range of hosts, from invertebrates andpoultry (Galvin, 1964) through to mice and man (Strubeet al., 2013); for all but the denitive (canid) species,these represent intermediate hosts which can, through

    see front matter 2013 Elsevier B.V. All rights reserved.rg/10.1016/j.vetpar.2012.12.032ra canis: Molecular basis of immun


    unology and Infection Research, University of Edinburgh, Ashworth Laboratcognition and evasion

    est Mains Road, Edinburgh EH9 3JT, United Kingdom

  • 366 R.M. Maizels / Veterinary Parasitology 193 (2013) 365 374

    predation, allow the parasite to reach its nal denitivehost species. Secondly, the larval stage is able to enter along-term developmental arrest, which allows it to sus-pend life cycle progression whilst in a paratenic host, and toresume macanid specital arrest opregnancy colostrum tet al., 2011)

    T. canis that are nits infectiviimpossible.longevity: iple, larvae were able t

    Within widely incluvous systemvisceral larvand Rocha, the brain acern in the(OT) a recorotoxocariaprevalence and ndinget al., 1985infected wicacy becauthe incompWisniewsk

    2. Immun

    Pathogesystem reatures associlipopolysachydrates. Ssentinel cepresence ofspecic resCurrently, fterns (PAparasite, buby the strothis infectioresponse isciated withPrete et al.,

    Such a a specic scytokines Iquently, IL-class-switceosinophilstion (Beavehuman beiulated by t

    parasite (Del Prete et al., 1991). However, no individual Tcell specic antigen or epitope has yet been dened fromT. canis.

    Recently, the distinction between innate and adap-arms o

    identily proequiri). Indee popnse t

    IL-5, earasiteected nd late4+ T cg thattive Tyeneratitive eostic lot reoyed.

    respeed, an

    reactin whiction inere arti-TESd, usinositiv3% in c

    of th et al.n trop; Magreportsz et a) and 9o 27% ) and esia (

    sis reme que

    relevations gcant

    isotypse, tistosomugh re

    larva is whetion anssibly

    as infed to tionallyappinganismturation to the adult stage only once reaching aes. Thirdly, even in female canids, developmen-ccurs so that larvae can dwell in tissues untiloccurs, and then migrate transplacentally or viao infect the foetal or newborn pup ( highly prevalent in all canid populations

    ot treated regularly with anthelmintics, andty to wild species renders elimination almost

    Furthermore, the arrested state has remarkablen experimentally infected monkeys for exam-remained viable in the tissues for 9 years ando infect mice on transfer (Beaver, 1962).the paratenic host, T. canis larvae can migrateding the liver, musculature and the central ner-, causing the well-characterised syndrome ofa migrans (VLM) (Beaver et al., 1952; Carvalho2011; Schantz, 1989). The propensity to invadend the eye has given rise to particular con-

    human population, with ocular toxocariasisgnised syndrome (Good et al., 2004), and neu-sis (NT) inferred from cognitive decits, higheramong epilepsy cases (Quattrocchi et al., 2012),

    larvae in post-mortem brain samples (Hill). Current options for treatment of humansth tissue-dwelling larvae are of uncertain ef-se of the covert nature of the infection andlete resolution of symptoms (Othman, 2012;a-Ligier et al., 2012).

    e recognition

    ns are recognised initially by the innate immunecting to intrinsically foreign molecular signa-ated with xenogeneic species, such as bacterialcharide, unmethylated DNA and fungal carbo-uch signals are essential for innate immunells, such as dendritic cells, to react to the

    infectious organisms and to initiate pathogen-ponses from the adaptive immune system.ew such pathogen-associated molecular pat-MPs) have been dened for any helmintht their existence in T. canis can be surmisedng adaptive immune response that occurs inn. The major feature of this adaptive immune

    production of T. canis-specic antibodies, asso- CD4+ T-helper type 2 cell (Th2) activity (Del

    1991).Th2 response is characterised by release ofubset of mediators, in particular the type 2L-4, -5, -10 and -13, during infection. Subse-4 promotes B cell differentiation and antibodyhing, while IL-5 drives the differentiation of, a marked feature of human Toxocara spp. infec-r et al., 1952). T cell responses to T. canis inngs are clearly of the Th2 type, and are stim-he excretorysecretory (ES) antigens of the

    tive withrapidout r2012innatrespoducethe pin inf10) ain CDcatinadap

    Gdendiagnern bemplwithbe usbodyand iinfec

    Thof anworlserop7 to 213.9%(Won50% i1987larly (Jaro2007ing t2008Indoncaria

    ThmostinfecsigniIgG4intenschisalthoceralissueinfecor posuchRelatfunctby trmechf immunity has become much more blurredcation of innate lymphoid cells, which canduce Type-2 cytokines (Neill et al., 2010) with-ng activation by dendritic cells (Smith et al.,ed, it has been known for some time that someulations of cells can participate in the Th2o T. canis, for example non-B-non-T cells pro-ven in T cell-decient nude mice infected with

    (Takamoto et al., 1995). Moreover, eosinophiliamice shows a biphasic response with early (day

    (day 21) peaks; while the later peak is absentell-decient mice, the earlier one is intact, indi-

    it is generated by the innate rather than thepe-2 response (Takamoto et al., 1998).ion of specic antibodies provides the mostvidence for infection and is the basis for alltests for toxocariasis; with ELISA and West-activity to T. canis ES (TES) antigens generallyHowever, the diagnostic eld is still evolvingct to the optimal target antigens that shouldd more critically to the interpretation of anti-vity to an infection which is frequently coverth symptoms do not necessarily correlate withtensity or antibody titre (Smith et al., 2009).e now extensive data on the seroprevalence

    antibodies in human populations around theg the established ELISA. In older studies,

    ity in Europe ranged from 3 to 7% in adults andhildren (Gillespie et al., 1993), while in the USA

    ose over 6 years of age were antibody-positive, 2008). Remarkably, seroprevalences exceededical settings such as th