malaria, monocytes, macrophages and myeloid dendritic...

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The adhesive phenotypes expressed by Plasmodium-falciparum-infected erythrocytes were previously thoughtsimply to permit sequestration of parasites in the peripheralcirculation. Recent work has illuminated how falciparum-infected erythrocytes may modulate the function of monocytes,macrophages and myeloid dendritic cells through the action ofhaemozoin from digested haemoglobin and through adhesionof infected cells to their surface.

Addresses*Molecular Parasitology Group, Weatherall Institute of MolecularMedicine, University of Oxford, John Radcliffe Hospital, Headington,Oxford OX3 9DS, UK; e-mail: [email protected]†Nuffield Department of Clinical Laboratory Sciences, University ofOxford and Blood Research Laboratory, National Blood Service, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK; e-mail: [email protected]

Current Opinion in Immunology 2002, 14:458–465

0952-7915/02/$ — see front matter© 2002 Elsevier Science Ltd. All rights reserved.

AbbreviationsCSA chondroitin sulphate ADC dendritic cellG6PD glucose-6-phosphate dehydrogenaseHA hyaluronic acidICAM-1 intercellular adhesion molecule 1LPS lipopolysaccharidePfEMP-1 P. falciparum membrane protein 1TSP thrombospondin

IntroductionThe vast majority of morbidity and mortality from malariais caused by infection with Plasmodium falciparum.Falciparum malaria is a major public health problemthroughout the tropical world where climatic conditionspermit replication of the parasite in Anopheles mosquitoes.In such regions, malaria is responsible for 1–3 milliondeaths per year, mainly in children [1•].

Human infection begins with the injection of sporozoitesfrom Anopheles mosquitoes. After replication within hepatocytes, merozoites are released into the circulation,and enter and multiply within erythrocytes. The parasitescan multiply approximately eight-fold every two days [2•].Within a short time a high proportion of erythrocytes maybe infected, comprising up to several grams of foreign antigens. The parasite life cycle is completed within thefemale Anopheles mosquito after the sexual forms of theparasite are ingested in a blood meal (Figure 1).

The presence of infected erythrocytes in the peripheralcirculation is noticeably cyclic as those infected cells in thesecond half of their erythrocytic cycle bind to a variety of

host ligands including CD36, intercellular adhesion molecule 1 (ICAM-1; CD54), thrombospondin (TSP),CD31, chondroitin sulphate A (CSA) and hyaluronic acid(HA), or rosette uninfected erythrocytes or clump platelets[3,4] (Figures 1,2). These adhesive phenotypes are collec-tively responsible for the phenomenon of sequestration ofinfected blood cells in the post-capillary venules and areassociated with the development of severe clinical diseaseincluding coma particular to falciparum malaria [5,6].Adhesion is mediated, at least in part, by a family of parasite-encoded antigens (P. falciparum membrane protein 1 [PfEMP-1]) on the surface of infected erythro-cytes [7]. These antigens contain functionally conservedadhesive domains that are nevertheless highly variableantigenically. Rapid, mutually exclusive expression of different variant PfEMP-1 proteins not only allows theappearance of heterogeneous adhesive phenotypes withina clone but also permits evasion of clinically protectivehumoral immune responses [8–10].

In endemic areas, infection with P. falciparum results in arange of outcomes from asymptomatic infection, throughmild disease, severe disease and death. Immunity is expo-sure-related and therefore age-related and occurs rapidly tosevere non-cerebral disease, more slowly to mild diseaseand probably never to asymptomatic infection [11,12]. Theprevalence of infection within a population is still rising inthose age groups in which the incidence of severe disease isalready declining [13]. High levels of TNF-α, IFN-γ, IL-6and IL-1 are more frequently observed in children suffer-ing from severe malarial disease than those suffering frommild disease or asymptomatically infected [14–17]. Theseobservations have led to the hypothesis that infections earlyin life result in inflammatory immune responses effectiveagainst the parasite but are also associated with immuno-pathology. With increasing exposure, immune deviationand immuno-regulation may reduce immunopathology during infection, with the exception of cerebral malaria.

Animal models and indirect evidence from clinical obser-vations suggest phagocytosis of infected red blood cells bysplenic macrophages is a critical component of hostdefence mechanisms against blood-stage parasites. Otherinnate immune responses, including the role of NK cellsand neutrophils, are less well defined. Specific host effectorresponses against the malaria parasites include cytotoxiclymphocytes recognising intra-hepatic parasites, and anti-bodies against parasite molecules; these antibodies inhibitinvasion of erythrocytes, stimulate antibody-dependantcytotoxicity or recognise the adhesive proteins (PfEMP-1)expressed on the surface of erythrocytes [18]. It is clearthat many of the adaptive immune responses would have

Malaria, monocytes, macrophages and myeloid dendritic cells:sticking of infected erythrocytes switches off host cellsBritta C Urban* and David J Roberts†

Malaria, monocytes, macrophages and myeloid dendritic cells Urban and Roberts 459

to be primed by antigen-presenting cells, amongst whichmyeloid dendritic cells (DCs) are probably importantbecause of their ability to stimulate naïve T cells [19].

It is clearly in the interest of the parasite, and more formally a source of selective advantage for strains of falciparum parasites, to develop methods to inhibitimmune and inflammatory responses, potentially harmfulto the parasite and the host. However, until recently thespecific mechanisms of modulation of host cell responseshave been poorly understood.

It has been assumed that the sole advantage of adhesion ofinfected erythrocytes to endothelium for malaria parasiteswas simply avoidance of splenic phagocytes. In this review,

we will concentrate on the recent studies demonstrating adirect modulation of leukocytes by malaria parasites andthe significance of these findings for the parasite, and theirunwilling and sometimes unfortunate human host.

Modulation of macrophagesMacrophages phagocytose malaria-infected erythrocytes. Itis intriguing that macrophages may not only ingest intactinfected erythrocytes but also extract parasites from recentlyinfected erythrocytes, leaving the erythrocytes to continue tocirculate [20,21]. However, these crucial defences are under-mined and manipulated during malaria infection.

Macrophage function is reduced in malaria infection [22].In an original series of studies, Paulo Arese and colleagues

Figure 1

The life cycle of falciparum malaria. (a) Humaninfection begins with the injection ofsporozoites from female Anophelesmosquitoes taking a blood meal. Withinhepatocytes, replication takes place within10–14 days to generate approximately10 000 merozoites per hepatocyte. Afterrupture of the hepatocyte, the infectivemerozoites are released in to the circulation,and enter and multiply within erythrocytes. Theparasites can multiply approximately eight-foldevery two days [2•] and so within a short timea high proportion of erythrocytes may beinfected, comprising up to several grams offoreign antigens. Asexual parasites maydifferentiate into sexual forms — gametocytes.The parasite life cycle is completed within thefemale Anopheles mosquito after the sexualforms of the parasite are ingested in a bloodmeal. (b) During the second half of theerythrocytic cycle, PfEMP-1 (the variantantigen) is expressed on the surface ofinfected erythrocytes. This family of proteins(possibly with other adhesive proteins)mediate adhesion of infected erythrocytes toendothelium on post-capillary venules.Infected erythrocytes may also form rosetteswith uninfected erythrocytes mediated indifferent strains by CR1 (CD35), ABO bloodgroup antigens, immunoglobulins andglycosamaminoglycans (GAGs). Some‘clumping’ strains are able to form largeaggregates of infected erythrocytes andplatelets, requiring expression of CD36 onplatelets. Finally adhesion of infectederythrocytes to leukocytes directly or indirectlyby via CD36 and CD51 (αv integrin of theαvβ3 or αvβ5 heterodimer) may modulate hostcell function. Endothelial and

placental adhesionCD36; TSP ICAM-1 (CD54)PECAM-1 (CD31)P-selectinCSAHA

Rosetting uninfectederythrocytesCRI (CD35)ImmunoglobulinsBlood group AGAGs

Clumping plateletsCD36

Adhesion to myeloiddendritic cellsand macrophagesCD36

Sporozoites

Merozoites Gametocytes

Merozoites

AsexualGrowth

Erythrocyte

Current Opinion in Immunology

(a)

(b)

Liver

460 Immunity to infection

have shown that inhibition of macrophage function, at leastin part, may be due to haemozoin — more colloquiallyknown as ‘pigment’ — a crystalloid polymer of haem moieties that accumulates during the erythrocytic cycle[23–25] (Figure 3a). They showed that ingestion of smallnumbers of infected erythrocytes containing haemozoininhibits further phagocytosis of infected erythrocytes orother substrates. Furthermore, the intracellular mecha-nism of pathogen killing, namely the generation ofsuperoxide radicals, was perturbed [26]. However, theingestion of more-recently infected erythrocytes in whichpigment had not accumulated was not associated with inhibition of macrophage function.

A potential mechanism of inhibition of cellular function by haemozoin is the generation of biologically active endo-peroxides — formed by peroxidation of arachadonicacid — including 4-hydroxynoenal and 15(R, S)-HETE(HETE is the abbreviation for 15-hydroxy-6, 8, 11,13-eicosatetraenoic acid) [27,28•]. These lipoperoxideshave been isolated from haemozoin and/or haemozoin-fedmacrophages and have been shown to inhibit macrophagefunction in vitro.

What are the clinical implications of these observations?Certainly the presence of pigment in circulating mono-cytes and neutrophils is associated with a poor outcome inThai adults [29] or severe disease in African children[30,31]. Hence it is not clear if this association is simply amanifestation of prolonged higher levels of malaria parasites or whether there is a causal relationship betweenintracellular pigment and more widespread cellular dys-function. More directly, impaired monocyte function may

explain the frequent association of bacteraemia in childrenpresenting with clinical malaria [32] and of malarialanaemia in children presenting with non-typhoid salmonellaspp. salmonella bacteraemia [33].

It has been suggested that altered recognition of infectederythrocytes by phagocytes is a mechanism of action of thegenetic traits that protect from severe malarial disease. Areseand colleagues have observed that macrophages are able torecognise infected erythrocytes from people carrying defectiveforms of the erythrocyte enzyme glucose-6-phosphate dehydrogenase (G6PD) at an earlier point in the growthcycle than infected erythrocytes with normal haemoglobin.It is therefore suggested that those with this trait clearinfected erythrocytes with less pigment and thus have lessinhibition of monocyte function compared with those withnormal G6PD activity [34••]. However, the recognition signals for these cells are not known and the hypothesis hasnot been tested in malaria patients.

More recently, an interesting and initially surprising series ofobservations from Kevin Kain and colleagues has providedanother mechanism for modulation of macrophage function.They observed that infected erythrocytes expressing theappropriate variant antigen (PfEMP-1) were phagocytosedby macrophages via CD36 without increasing or priming forsecretion the pro-inflammatory cytokine, TNF-α [35••](Figure 3b). This group has more recently shown that proliferation-activated receptor γ-retinoic acid X receptoragonists and 9-cis-retinoic acid — a metabolite of vitamin A — increase the levels of CD36 expression on macrophagesand the phagocytosis of infected erythrocytes while reducingthe secretion of pro-inflammatory cytokines [36,37•].

The apparent anti-inflammatory effect of adhesion ofinfected erythrocytes may have a profound effect on theoutcome of malaria infection. These observations suggestthe inhibition of phagocytosis and inhibition of otherinflammatory responses, mediated by adhesion of infectederythrocytes to monocytes, may facilitate survival of bothparasite and host.

Modulation of dendritic cellsIt is reasonable to assume that DCs play a pivotal role in initiating immune responses to malaria. We observed that falciparum-infected erythrocytes could bind to the surface ofmyeloid DCs in vitro and profoundly modulate the matura-tion and function of DCs. Infected erythrocytes could inhibitthe normal upregulation of MHC class II molecules, adhesionmolecules (e.g. ICAM-1) and co-stimulatory molecules(CD83 and CD86) on DCs after stimulation with lipopoly-saccharide (LPS). The ability of DCs to stimulate not onlyallogenic but also antigen-specific primary and secondaryT-cell responses was profoundly reduced [38••,39] (Figure 3c).

Recently, we have shown that the receptors on the surfaceof DCs mediating this inhibitory effect are CD36 andCD51 (αv integrin, a component of αvβ3 and αvβ5 integrin

Figure 2

The adhesive phenotypes of infected erythrocytes. Faliciparum-infectederythrocytes express various adhesive phenotypes. Here the adhesivephenotypes found in isolates from patients with malaria arerepresented in a semi-quantitative Venn diagram. The majority ofisolates bind to CD36 and/or TSP. In addition some isolates bindvariously to ICAM-1 (CD54) and/or CD31 or are able to rosetteuninfected cells or to clump platelets. Those parasites binding to CSAand HA are found more frequently in placental isolates and the majorityof these isolates do not bind to CD36.

Cytoadherence phenotypes in wild-type isolates

CD36/TSP

CSA

HA

CD31ICAM-1

Rosetting

Plateletclumping



Figure 3

(a)

(b) (c)

2 µm

2 µm10 µm

The interaction of monocytes and myeloid DCs with infected erythrocytesand haemozoin. Transmission electron microphotographs of (a) amonocyte with numerous ingested particles of haemozoin; (b) amonocyte with adherent falciparum-infected erythrocytes (the ruffling ofthe monocyte membrane can be seen between the infected erythrocytes);and (c) two falciparum-infected erythrocytes adhering to a myeloid DC.

The close apposition between the plasma membrane of the DC and theinfected erythrocyte can be clearly seen. Pictures are included courtesy ofDavid Ferguson (Nuffield Department of Clinical Laboratory Sciences),Dominic Kwaitowski (Nuffield Department of Paediatrics) and TonyBerendt (Nuffield Department of Clinical Medicine), University of Oxford,and are reproduced with permission from David Ferguson.

heterodimers). Ligation of CD36 and/or CD51 mimics theinhibition of DCs by infected erythrocytes [40•]. It wasstriking that these molecules are not only receptors forinfected erythrocytes but are also involved in the recognitionof apoptotic cells by phagocytes.

In our experiments it was apparent that apoptotic cells alsoinhibit the maturation and function of DCs. Moreover,infected erythrocytes, ligation of CD36 and/or CD51 orapoptotic cells — including apoptotic DCs — reduced thesecretion of IL-12 and increased the secretion of IL-10 butdid not significantly perturb the secretion of TNF-αduring maturation of DCs [40•]. These data suggested thatthe malaria parasite has evolved an adhesive phenotype to enable an infected erythrocyte to mimic at least some of the adhesive ligands of apoptotic cells. Indeed, the

downregulation of TNF-α secretion by macrophages bindingto infected erythrocytes via CD36 (see above) is reminiscentof apoptotic cells binding to human monocytes andmacrophages [41] (Figure 4).

Is DC function impaired during malaria infection? Thenumber of CD83+ peripheral blood DCs was not signifi-cantly different in healthy children and in children withmalaria. However, the percentage of HLA-DR+ DCs inperipheral blood was significantly reduced in childrenwith malaria [42]. These data gave only a gross indicationof the function of DCs in falciparum malaria as they didnot distinguish between myeloid and plasmacytoid DCsnor did they examine the kinetics of DC turnover andtheir capacity to stimulate T cells. Furthermore, the relative effects of malaria pigment and adhesion of


Figure 4

LPSMonocyte-conditioned

mediumCD40 ligand

Malaria-infectederythrocytesApoptotic cellsLigation of CD36

Ligation of CD51

LPSIFN-γ

Malaria-infectederythrocytesApoptotic cellsLigation of CD36

Activated macrophage

Enhanced secretion of pro-inflammatory cytokines

including TNF-α, IL-6 and IL-1

Modulated macrophage

Enhanced secretion of anti-inflammatory cytokines including IL-10 and TGF-β

Modulated dendritic cell

Unresponsive T cells IL-10 secretion

Immature dendritic cell Monocyte/macrophage(a) (b)


Immunstimulatory dendritic cell

Type 1 and Type 2 responsesIL-12 secretion

Modulation of DCs and monocytes/macrophages by infectederythrocytes and by apoptotic cells. (a) Immature myeloid DCsexposed to LPS, monocyte-conditioned medium or CD40 ligandmature and express high levels of MHC class II molecules, adhesionand co-stimulatory molecules, allowing them to activate T cells.However, if immature DCs are exposed to falciparum-infectederythrocytes or apoptotic cells they are modulated and do notstimulate primary or secondary T-cell responses. Modulation of DCsmay be achieved by ligation of CD36 or CD51 (αv integrin). MatureDCs secrete high levels of IL-12; by contrast modulated DCs secrete

IL-10. (b) Monocytes and macrophages are also modulated byfalciparum-infected erythrocytes and by apoptotic cells. Whenactivated by LPS or IFN-γ, macrophages secrete inflammatorycytokines including TNF-α. Exposure to falciparum-infectederythrocytes or ligation of CD36 does not induce TNF-α secretion.However, after ingestion of apoptotic cells, secretion of the anti-inflammatory cytokines IL-10 and transforming growth factor β (TGF-β)is enhanced. Extensive functional impairment of macrophage functionmay also follow ingestion of haemozoin from infected erythrocytes (not shown).

infected erythrocytes on myeloid cell function have not been established.

Animal modelsAs the story of modulation of host cell function by falci-parum-infected cells and their products has unfolded,there has been some interest to see whether similar effectsare observed in animal models of malaria. These modelsare somewhat limited by the peculiar host-restriction ofmalaria parasites to primates, rodents, birds and lizards.The rodent malaria P. chaubaudi chaubaudi in laboratorymice represents a useful model of the early inflammatoryresponse in human malaria. Furthermore, the parasite maysequestrate in heart, lung, liver and spleen, but not thebrain of mice and so provide a model for severe non-cerebralmalaria [43–45].

Do erythrocytes infected with this rodent malaria parasiteinhibit the function of murine myeloid DCs? It appearsnot. After exposure to P. c. chaubaudi-infected erythrocytes,murine DCs mature normally and stimulate T-cell responses.Furthermore, they produce TNF-α (over 2 hours), IFN-γand IL-12 (over 10 hours) [46•]. These data contrast toobservations of the downregulation of IL-12 but upregulationof IL-10 secretion by human myeloid DCs after exposureto erythrocytes infected with the falciparum parasites [40•].

By contrast, it has been recently reported that murinemyeloid DCs, having ingested apoptotic cells, not onlydownregulate secretion of IL-12, but also show a reducedcapacity to stimulate antigen-specific T-cell responses[47•]. Together, these data suggest that at the cellular levelparallels exist between the modulation of human andmurine myeloid DC function by apoptotic cells but not bymalaria-infected erythrocytes. In humans, definition of thereceptors used by phagocytes to recognise and ingest apoptotic cells or falciparum-infected erythrocytes are wellcharacterised. Although chaubaudi-infected erythrocytesexpress variant antigens [48], can cytoadhere [43] and maybind to CD36 [44], is remains to be seen whether thesecharacteristics are mediated by the same protein (families)or similar properties of different protein (families). Furtherstudies on the molecular interaction of P. c. chaubaudi-infected erythrocytes or indeed apoptotic cells withmurine macrophages or DCs are awaited with interest.

ConclusionsHow do these observations of the modulation ofmacrophage and DC function by falciparum-infected erythrocytes explain the pathophysiology of malaria andwhat hypotheses do they generate for future studies?

In the older literature, impairment of immune responses tovaccine antigens has been described in children vaccinatedduring malaria infection [49,50]. Furthermore, the associationof Burkitt’s lymphoma — where unchecked Epstein–Barrvirus (EBV)-derived proliferation of B lymphocytes leadsto malignant transformation — with malaria-endemic areas

suggests suppression of immune responses by malariainfection [51,52]. We now have evidence from in vitrostudies that the immunosuppressive effect(s) may becaused by pigment and by adhesion of infected erythro-cytes to antigen-presenting cells.

The role of pigment and the lipoperoxides generated bythe catalytic effect of pigment in the outcome of malariainfection is not clear. However, the association of pigment-containing monocytes and neutrophils in the peripheralblood with the severity of clinical disease is consistent with a causal relationship. If this effect is established then inhibiting this pathway of cellular damage may allow amelioration of malaria morbidity and mortality.

The at-first-sight counter-intuitive effect of adhesion toCD36 and/or TSP on host cell function makes sense of thepattern of adhesive phenotypes expressed by P. falciparum-infected erythrocytes. The vast majority of isolates fromthose suffering from malaria can bind to CD36 and to TSP[53–56] (Figure 2). Furthermore, a functional CD36-bindingdomain is conserved in the majority of variant antigens thatcan be expressed on the surface of infected erythrocytes,although the sequence of this domain is highly variable.These data support the importance of adhesion to CD36for the success of and survival of parasite strains.

What is the significance of the adhesion of infected erythrocytes to CD36 for the host? Infected erythrocytes withthe highest affinity for CD36 binding are more frequentlyfound in isolates from patients with mild disease comparedwith isolates from patients with severe disease [55,56]. Theseobservations suggest that adhesion of infected erythrocytes toCD36 may reduce the pro-inflammatory response to the para-site and so influence the outcome of severe disease (Figure 4).

It is tempting to speculate that the other common adhesivephenotypes of falciparum-infected erythrocytes, such asadhesion to ICAM-1, CR1 (C35) and CD31, may also mod-ulate host cell function (Figure 2). Indeed, the pattern ofadhesive phenotypes expressed by infected erythrocytes,once thought to be extensive, is in fact quite restrictedgiven the large number of potential host moleculesexpressed on endothelium and leukocytes.

These insights of the modulation of host-cell function bycytoadherence of malaria parasites also suggest that adhesivephenotypes expressed by other pathogens may also represent‘switching’ and not just ‘sticking’. Many other pathogensdo adhere to αvβ3 integrins including: two picornaviruses(coxsackie A9 and foot and mouth virus); Neisseria menigitidis;Mycobaterium avium and M. intracellulare; and finally thespirochete Borrelia burgdorferi [57–61]. The immuomodu-latory effects of these specific host-cell interactions havenot been described.

In summary, studies of the modulation of the immune system by malaria parasites have revealed pathways of


immune modulation by apoptotic cells which may beimportant for the maintenance of peripheral tolerance toself. It appears that malaria parasites use this physiologicalpathway to subvert innate and acquired immune responsesagainst the parasite (Figure 4). The underlying mechanismsof modulation of myeloid DCs and of macrophages andsubsequently of T-cell function remain to be elucidated.One would predict these mechanisms will be of continuedbiological interest and potentially of medical importance.

AcknowledgementsBritta Urban is supported by the Wellcome Trust and thanks Chris Newboldfor support. David Roberts is supported by the National Blood Service, theUniversity of Oxford and the Howard Hughes Memorial Institute.

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