review: innate immunity to tropical theileriosis

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2008 14: 5Innate ImmunityJabbar S. Ahmed, Elizabeth J. Glass, Diaeldin A. Salih and Ulrike Seitzer

Review: Innate immunity to tropical theileriosis

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INTRODUCTION

Tick-borne diseases of livestock are responsible for hun-dreds of millions of dollars loss per year in tropical andtemperate areas where they pose a problem. Global loss hasbeen estimated at US$ 7–13.9 billion a year and US$ 18.7billion per annum.1,2 The protozoan parasite Theileriaannulata is the causative agent of the tick-borne diseasetropical theileriosis in cattle, causing morbidity and lossof productivity in indigenous cattle and severe, and oftenlethal, disease in imported high-grade cattle and cross-breeds in a wide geographic distribution ranging fromthe Mediterranean littoral regions of Europe and Africato the Near and Middle East to India and China inAsia.3,4 The disease acts as a major constraint to live-stock production and improvement. This is of particularrelevance when naïve exotic cattle, such as Holstein, areused to improve the productivity, since these animals areextremely susceptible to this infection.

The disease is transmitted only after cyclical develop-ment in the tick of the genus Hyalomma, which transmitT. annulata trans-stadially, stage to stage, where infectednymphs alimentarily transmit the disease as adults.5 Theschizogony stage begins when Theileria sporozoites(infective stage) are injected into the vertebrate host with

saliva of infected vector ticks (nymphs or adults) duringthe feeding process. After injection, T. annulata sporo-zoites rapidly invade macrophages and B-lymphocytespreferentially.6–8 The sporozoite initially resides in a vac-uole, but the membrane of the vacuole disappears at 24-hpost infection, leaving the parasite free in the cytoplasmand associated with the host’s spindle apparatus.9 Insidethe leukocyte, the parasite develops into the macroschizontstage (Fig. 1) which induces transformation and prolifera-tion of the host cell.10 The subsequent microschizont stagedifferentiates to merozoites, which are released upon host cellrupture, becoming free to penetrate into erythrocytes8–10days post infection.11 Inside the red blood cell, the para-site develops into the piroplasm stage. Piroplasms repli-cate inside the red blood cells and both this stage and newlyformed merozoites proceed to infect other red blood cells.The piroplasm stage is infective to ticks.

Two unique features of T.annulata are its ability toexist free in the host cell cytoplasm and its ability totransform the host cell reversibly, leading to uncon-trolled proliferation of the parasite and the host cell. Theimmediate exposure of the parasite membrane to thehost cell cytoplasm offers possibilities for the parasite tointerfere with host cell signalling pathways, which mayplay a role in the transformation process. Indeed, the

Review

Innate immunity to tropical theileriosis

Jabbar S. Ahmed1, Elizabeth J. Glass2, Diaeldin A. Salih1, Ulrike Seitzer1

1Division of Veterinary Infection Biology and Immunology, Research Center Borstel, Borstel, Germany2Department of Genetics and Genomics, Roslin Institute and Royal (Dick) School of Veterinary Studies, Roslin Biocentre, Midlothian, UK

The intracellular protozoan parasite Theileria annulata causes a severe, and often fatal, disease of pure and cross-bredcattle in tropical and subtropical countries. The present review refers to the importance of innate immunity as far as itis known to date in this infectious disease. Specifically, macrophages and the mediators produced by these cells areoutlined. In addition, the latest findings concerning cattle breed differences in susceptibility to T. annulata infection inrelation to macrophage activation are discussed.

Keywords: Theileria annulata, tropical theileriosis, innate immune response, resistant cattle breed

Received 19 October 2007; Revised 15 November 2007; Accepted 18 November 2007

Correspondence to: Jabbar S. Ahmed, Division of Veterinary Infection Biology and Immunology, Research Center Borstel, Parkallee 22, 23845Borstel, Germany. Tel: +49 (0)4537 188428; Fax: +49 (0)4537 188627; E-mail [email protected]

14(1) (2008) 5–12

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parasite influences activation of the NF-κB, MAPK andPI3-K-PKB pathways.12–14Among the downstream conse-quences of activation of these pathways are the up-regulationof pro-inflammatory cytokines which are expressed at highlevels in infected cells and the up-regulation of major histo-compatibility complex (MHC) class II molecules.15,16

It is, as yet, unclear how the parasite mediates trans-formation, although a few parasite-encoded moleculeswhich contain DNA-binding motifs have been localizedin the host nucleus and may thus be candidates as modu-lators of host gene expression.17 In addition, it is postu-lated that conserved proteins on the outer membranesurface of the parasite or secreted proteins representideal candidates for parasite–host-cell interactions. Untilnow, some Theileriaproteins have been described whichare inserted into the schizont’s membrane.18–21 In fact,for all described Theileriaproteins exhibiting character-istics for the potential to interact with host cell proteins,an interacting host cell partner has not been identified todate. Recently, however, a Theileria protein, TaSE, wasdescribed which is expressed in the parasite, on the para-site surface and is secreted into the host cell cytoplasm.22

The association and distribution of TaSE with compo-nents of the mitotic spindle during mitosis and cytokine-sis suggest that it may have a possible function in theequal distribution of the parasite into daughter cells dur-ing host cell mitosis.

Immunity to T. annulata infection

Cattle which survive an infection with T. annulata aresolidly immune against the same and, to a certaindegree, against a homologous parasite strain.23 It is wellestablished that both antibody-dependent and antibody-independent mechanisms are involved in the protectionagainst tropical theileriosis. Antibodies to all stages aredetectable at a later phase of the infection and thus at atime when the infection has been controlled. No anti-body activity has been detected against the surface ofparasitized leukocytes or erythrocytes. However, anti-bodies are able to neutralize the infectivity of the sporo-zoites but, on the other hand, do not prevent initiation ofan infection. However, T-cells play the crucial role ininduction and maintenance of this immunity. Based onthe cytokine profile and lytic effect of the T-cells, itseems that both CD4+- and CD8+-T cells are involved inthe mediation of such an immunity.24–27 Presumably,cytotoxic- and helper-T-cells recognize parasite antigens,which are presented by the infected cells via MHC I andMHC II, respectively. In vitro, it has been shown thatboth helper- and cytotoxic-T-cells are responding to theinfected cells: helper T-cells proliferate and produceinterleukin 2 (IL-2) and interferon-γ (IFN-γ);27 IL-2 is con-sumed by the cytotoxic T-cells for their clonal expansion

and subsequent killing of their target cells in an MHC classI restricted manner. The generation of cytotoxic T-cells isclosely related to the control of the infection.24–26

Apart from adaptive immunity, there is growing evidencethat innate immunity also plays an important role in protec-tion against T. annulata infection. Innate immunity (naturalor native immunity) mediates the initial protection againstinfection, it is always present in healthy individuals, pre-pared to block the entry of microbes and to eliminatemicrobes that do succeed in entering host tissues rapidly.28

The first line of defense in innate immunity is provided byepithelial barriers and specialized cells and natural antibi-otics present in epithelia, all of which function to block theentry of microbes. If microbes do breach epithelia and enterthe tissues or circulation, they are attacked by phagocytes,specialized lymphocytes called natural killer (NK) cells,and several plasma proteins, including the proteins of thecomplement system. In addition to providing early defenseagainst infections, the innate immune response enhancesadaptive immune responses against the infectious agents.

This review will focus on the role of innate immunityin tropical theileriosis so far as it is known to date.

Cytostatic acting mononuclear cells

The massive, uncontrolled cell proliferation observedduring infection with Theileria schizonts is the most

6 Ahmed, Glass, Salih, Seitzer

Fig. 1. T. annulata schizont infected cell. (A) Giemsa stain showingschizont nuclei in the cytoplasm of an infected cell. (B) Nomarski optics ofa T. annulata schizont infected cell. (C) Same cell stained with fluorescentnucleic acid stain (propidium iodide, red) depicting host cell and parasitenuclei. The schizont was visualized using an antibody directed against theparasite membrane and a fluorescently labelled second antibody (green).(D) Merged image of (B) and (C). Size bars 10 µm.



important pathogenic aspect of theileriosis. The intracel-lular stage of the parasite is intimately linked to theextensive pathology seen in susceptible animals. In addi-tion, cells infected by T. annulata induce polyclonalnaïve T lymphocyte proliferation both in vivo and invitro and these aberrantly activated T lymphocytesswitch to a Th1 phenotype, producing large quantities ofIFN-γ (Fig. 2).29,30 The draining lymph node becomesgrossly enlarged as a result of the expansion of bothinfected cells and T cells. The abnormally high levels ofIFN-γ together with excessive production of pro-inflam-matory cytokines are most likely the main causes of par-asite induced pathology.31,32 A non-specific proliferationof T-cells has also been observed in an in vitro mixedlymphocyte culture in which parasite-containing cellshave been used to stimulate non-specifically their unin-fected counterparts to proliferate and to produce IL-2and IFN-γ(Fig. 2).26,27,33It has been suggested that suchcytokines contribute to the pathogenesis of tropical thei-leriosis by enhancing the growth of the infected cells.34

How may growth factors contribute to enhancing theproliferation of the parasitized cells? More than twodecades ago, it was shown that Theileria-infected cellsexpress interleukin-2 receptor (IL-2R) and that theirgrowth can, under certain conditions, be enhanced by anexogenous growth factor like IL-2.35,36 Thus, it is possi-ble that IL-2 produced in vivo by uninfected proliferat-ing T-cells might contribute to the growth of theparasitized cells through binding to the IL-2R in aparacrine manner. Based on this, Ahmed et al.34 sug-gested that IL-2 and IL-2R may play an important role inthe pathogenesis of theileriosis caused by T. annulata byenhancing the growth of the parasitized cells (Fig. 2).

In essence, inhibition of non-specific cell prolifera-tion appears to be an important step toward the controlof the infection by reduction of the pressure of theinfection which, in turn, allows the development of aspecific and effective immune response. This hypothesiscan be supported by a number of observations reportedby several groups giving a hint for an important role of

Innate immunity to tropical theileriosis 7

Fig. 2. Immune response during acute phase of infection with T annulata. Infected cells produce TNF-αwhich stimulates NK-cells to produce IFN-γ.Infected cells also unspecifically stimulate naive T-cells leading to aberrant proliferation and production of IFN-γ and IL-2. These cytokines contribute tothe pathogenesis of tropical theileriosis by establishing infection and enhancing the growth of the infected cells.



monocyte/macrophages in controlling non-specific cellproliferation.

In an in vitro mixed lymphocyte culture, peripheralblood mononuclear cells (PBMCs) of immunized ani-mals inhibited the growth of the parasitized cells in anMHC-independent manner.26 Hence, autologous as wellas allogeneic parasite containing target cells were inhib-ited in their growth as determined by reduced incorpora-tion of [3H]-thymidine. Interestingly, PBMC of naiveanimals did not interfere with the growth of the para-sitized cells, indicating that, within the PBMCs ofimmune animals, there is a population which exerts acytostatic effect on the growth of the parasitized cells.26

Based on these observations, these cells were designatedas cytostatic acting cells (CACs) which may act as follows:

1. They induce the lysis of the infected target cells whichthen are no more able to incorporate [3H]-thymidine.

2. They secrete NO which inhibits replication of theparasites leading to apoptosis of the infected cell assuggested by Visser et al.37

3. They produce TNF-αwhich then inhibits cell prolifer-ation. Contrary to this supposition, however, recom-binant TNF-α added to cultures of T. annulata infectedcells does not interfere with growth of these cells.38,39

The role of suppressive mediators produced by macro-phages which either directly kill the parasites or inhibitthe establishment of new infection by interfering withthe process of parasite differentiation in parasitized hostcells will be discussed below.

In well-designed in vitroexperiments, Preston andBrown40 demonstrated that monocytes harvested fromanimals undergoing resolving infections not only inhibitthe growth of the infected cells but also non-specificproliferation of lymphocytes activated by the infectedcells (Fig. 3). The contribution of these suppressivemacrophages to control the infection may be throughreducing the aberrant T-cell proliferation which conse-quently leads to less IL-2 and IFN-γproduction, both ofwhich have been postulated to enhance the growth of theparasitized cells.30,41 In turn, this reduces the infectionpressure, allowing the establishment of an effective andspecific immune response directed primarily against theschizont stage of the infection.

In an approach to induce a non-specific protectionagainstTheileria annulata infection in cattle, Manickamet al.42 inoculated cattle subcutaneously with killedCorynebacterium parvum as an adjuvant and then chal-lenged them with T. annulata-infected ticks. All immu-nized animals survived the challenge infection while thecontrols died, indicating that C. parvum induced a non-


Fig. 3. Induction of cytostatic acting cells in resolving infection with T. annulata. Activation of uninfected macrophages leads to the production of NO andcytokines by these cells. NO and suppressive cytokines kill the schizont and act cytostatically on proliferating schizont-infected cells, respectively.Moreover, activated macrophages suppress the aberrant polyclonal proliferation of unspecific T-cells.



specific protection.42 In a similar experiment, the sameauthors found a significant decrease in neutrophils and asignificant increase in monocytes in calves who survivedthe infection.43 The results may indicate that C. parvumused as an immunostimulant activated monocytes whichsuppressed the establishment of a lethal infection.

Natural killer cells (NK-cells)

NK-cells have been shown to be implicated in the patho-genesis of Theileria parvainfection, a parasite closelyrelated to T. annulata. Their role, however, in T. annu-lata infection is not very clear, albeit their involvementin the lysis of the parasitized target cells in an MHC-independent manner.24 These authors found that NK-cellactivity coincides with the healing stage of a sporozoiteinfection. In addition, it is well established that NK-cellsproduce IFN-γto activate uninfected macrophages invitro. In turn, these activated macrophages produce anumber of cytokines (IL-1, IL-6 and TNF-α), some ofwhich can inhibit the establishment of newly infectedcells by preventing further development of trophozoitesto schizonts, which are known to induce and maintainthe transformed state of the infected host cells.39

Cytokines and nitric oxide

Many of the clinical symptoms of tropical theileriosishave been associated with pro-inflammatory cytokineactivity. T. annulata infected cells express mRNA for anumber of such cytokines including IL-1α, IL-1β, IL-6and TNF-α.16 It has been shown that cell lines express-ing higher amounts of pro-inflammatory cytokinesinduce a more severe course of infection upon inocula-tion into naïve animals in which an aberrant T-cell pro-liferation and an abundant production of IFN-γ takeplace.30 On the other hand, TNF-α and IFN-γmay beplaying an essential role in controlling the infection.Both these cytokines have been shown to interfere withthe differentiation of the trophozoites to schizonts, thuspreventing the establishment of new infections.39 IFN-γcan, on the other hand, activate non-infected macro-phages which, in turn, inhibit not only the proliferationof the parasitized cells but that of T-cells non-specifi-cally responding to a stimulation by T. annulata infectedcells. Thus the role of cytokines appears to be a very del-icate one depending on the time of production and site ofaction, which must be well balanced during the infec-tion. In acute cases of the infection they may be destruc-tive, whereas their role after challenge is part of theprotective immune response.

A variety of cells are involved in the production of IFN-γincluding T-cells and NK-cells. TNF-αcan be produced byinfected cells and/or activated non-infected macrophages. Inaddition to TNF-α, activated macrophages can secrete nitricoxide (NO) which has been shown to prevent the invasion ofhost cells by sporozoites, to inhibit the proliferation of the

parasitized cells and to induce their apoptosis, most probablythrough destroying the schizonts.37

Breed differences in susceptibility to T. annulatainfection

Exotic cattle breeds are extremely susceptible to tropicaltheileriosis caused by T. annulata. Thus, while the infec-tion induces severe, and often fatal, diseases in suscepti-ble Bos taurus and cross-bred cattle, Bos indicusmanagethe infection better and develop a solid immunity, pre-sumably due to the activation of innate immunity.44

Bakheit and Latif45 carried out studies to assess theinnate resistance of the indigenous Kenana breed of cat-tle in the Sudan to tropical theileriosis. They found thatthe percentage of schizont parasitosis in the Kenana cat-tle was reduced by 70% compared to the Friesian calves.The percentage of piroplasm parasitemia was also sig-nificantly lower in the Kenana calves. The rate of whiteblood cell reduction was significantly greater in theFriesian calves. Of the Kenana cattle, 78% recoveredspontaneously, and only 22% required treatment com-pared to 100% mortality in the Friesian controls. Thesedifferences were attributed to the high rate of schizontmultiplication in the control cattle and, on the otherhand, ability of the Kenana cattle to limit the macrosch-izont replication, resulting in less severe damage to thelymphoid tissue during the acute phase of the disease.

Recently, it was shown in a kinetic study that thedivergence in disease progression following experimen-tal infection with T. annulata, between a naturally toler-ant B. indicus breed and a susceptible Bos taurus breedoccurs during the macroschizont stage.32 In addition,high systemic levels of macrophage pro-inflammatorycytokine dependent acute phase proteins are produced inthe susceptible breed whereas the tolerant breed pro-duces much lower levels. These results led to thehypothesis that macrophages in a naturally tolerant B.indicus breed are able to control the ‘cytokine storm’that is so devastating in susceptible B. taurus breeds.46

Armed with this information, it should theoretically bepossible to identify the genes underlying the observedresistance to T. annulata, but to perform a conventionalwhole genome shotgun study would be logistically diffi-cult, expensive and take many years. Instead a differentapproach, non-biased and ‘global’ in its range, transcrip-tomic profiling, was applied. It was reasoned that theunderlying resistance is likely to be expressed ininfected macrophages and, as a result, may alter theinteractions between infected cells and other immune cells,particularly T cells. To do this, a bovine cDNA microarraywas created using clones derived from a specially creatednormalised bovine macrophage library.47 This library wasderived from a pool of macrophages from both the resistant




and susceptible breeds, that had been activated with variousmacrophage activators, as well as infected with T. annulatato ensure that as many relevant transcripts as possible wererepresented on the microarray.48

It was shown that macrophages from breeds differingin resistance to T. annulata have very different transcrip-tional responses to infection with the parasite.49 Out ofthe 5000 genes represented on the microarray, 156 weredifferentially expressed between the breeds, with about25% of these having no known function, and 10 genesunique to the macrophage library. This latter result isperhaps surprising given the wealth of cattle clones andexpressed sequence tags in the public domain, but pre-sumably reflects the relative lack of bovine librariesderived from immune tissue, especially those derivedfrom infected or activated cells. Of the known genes,around 30% are associated with the plasma membrane orwith the extracellular space and about 20% with the cellnucleus, the majority being transcription factors.Significantly, striking differences were discovered in

expression of genes encoding proteins associated with T-cell interactions including signal-regulatory proteinalpha (SIRPA) and MHC DQ. Many of these differenceswere inherent differences in macrophage gene expres-sion between the two breeds, and the challenge is now todiscover what the underlying polymorphisms are thatdetermine these intriguing breed differences.

Currently, investigations are aimed at analysing earlytime points during the host–pathogen interaction andplan to utilise a parasite oligonucleotide microarraywhich encompasses all of the open reading frames of therecently sequenced T. annulata genome in order tounderstand better how the parasites can modulate thehost transcriptome for their own advantage. In the futureit is anticipated this approach lead to new targets for dis-ease control.50 Indeed, it is to be hoped that the burgeon-ing genomic information for both the cattle host and theparasite will further increase our understanding of theinteractions between T. annulata and the bovine innateimmune response.51


Fig. 4. Protective immunity in T. annulata infection. Interplay of innate and adaptive immune responses lead to protective immunity (detailedexplanation in Summary).



SUMMARY

In primary T. annulata infections, the schizont stage iscontrolled by the innate immune response (NK-cells,macrophages) and the adaptive cellular immuneresponse (cytotoxic T cells, T-helper cells).41 Both T- andB-lymphocytes are activated during the infection with T.annulata. Antibodies to all stages are detectable at a laterphase of the infection and thus at a time when the infec-tion has been controlled.52 No antibody activity has beendetected against the surface of parasitized leukocytes orerythrocytes. However, antibodies are able to neutralizethe infectivity of the sporozoites but, on the other hand,do not prevent initiation of an infection. T-cells partici-pate in immunity to T. annulata by acting as cytotoxic Tlymphocytes (CTLs) and as T-helper-lymphocytes.Thus, T-helper cells produce IL-2 which is required forthe clonal expansion of CTLs and IFN-γ which activatesmacrophages to produce NO.53 The latter destroys theschizonts within the infected cells. CTLs kill theirinfected target cells in an MHC class I-restricted manner.Cytokines are also required for the induction of parasite-specific antibodies. The role of NK-cells is not clear.They may act as effector cells in controlling the infectionby unspecific lyses of parasite-containing cells or theymay activate macrophages via production of IFN-γ.Cytostatic acting macrophages have been described toinhibit the in vitro growth of T. annulata-infected cells(Fig. 4).

ACKNOWLEDGEMENTS

This work was supported, in part, by the EU-fundedIntegrated Consortium on Ticks and Tick-BorneDiseases (ICTTD-3; contract number 510561) andADDAV (ICA4-1999-30151), BBSRC and WellcomeTrust. We thank colleagues at the Division of VeterinaryInfection Biology and Immunology, Research CenterBorstel, Roslin Institute and Ark-Genomics, particularlyKirsty Jensen, for the macrophage array work.

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review: innate immunity to tropical theileriosis

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