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VAR2CSA and protective immunity against pregnancy-associated Plasmodium falciparum malaria

Published online by Cambridge University Press:  25 October 2007

L. HVIID  and
A. SALANTI
L. HVIID*
Affiliation:
Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark
A. SALANTI
Affiliation:
Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark
*
Address for correspondence: Lars Hviid, Centre for Medical Parasitology, Department of Infectious Diseases M4701, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. Fax +45 35 32 78 51. E-mail: lhcmp@rh.dk
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Summary

People living in areas with stable transmission of P. falciparum parasites acquire protective immunity to malaria over a number of years and following multiple disease episodes. Immunity acquired this way is mediated by IgG with specificity for parasite-encoded, clonally variant surface antigens (VSA) on the surface of infected erythrocytes (IEs). However, women in endemic areas become susceptible to P. falciparum infection when they become pregnant, particularly for the first time, regardless of previously acquired protective immunity. This conundrum was resolved when it was observed that the selective placental accumulation of IEs that characterizes pregnancy-associated malaria (PAM) is caused by an immunologically and functionally unique subset of VSA (VSAPAM) that is only expressed by parasites infecting pregnant women, and that protective immunity to PAM is mediated by IgG with specificity for VSAPAM. In this review we summarize the research leading to the identification of the distinctly structured PfEMP1 variant VAR2CSA as the dominant PAM-type VSA and as the clinically most important target of the protective immune response to placental P. falciparum infection.

Keywords

AntibodiesimmunitymalariaPlasmodium falciparumpregnancyVAR2CSAvariant surface antigens

Information

Type
Research Article
Information
Parasitology , Volume 134 , Special Issue 13: PARASITES IN PREGNANCY , December 2007 , pp. 1871 - 1876
Copyright
Copyright © Cambridge University Press 2007

INTRODUCTION

Plasmodium falciparum malaria is both the commonest and most serious form of malaria affecting humans, and is an infection of colossal medical and economic consequence (Greenwood and Mutabingwa, Reference Greenwood and Mutabingwa2002; Miller et al. Reference Miller, Baruch, Marsh and Doumbo2002; Sachs and Malaney, Reference Sachs and Malaney2002). In areas of intense parasite transmission, severe P. falciparum malaria is concentrated among infants and young children, because acquisition of protective immunity causes malaria-related mortality and severe morbidity to decrease with increasing age. However, development of immunity is slow, and substantial protection is only achieved after a number of disease episodes. Even then, immunity is partial and though severe morbidity is rare among adults, sterile protection is probably never achieved. Several studies have documented the efficacy of passive immunization of malaria patients with IgG from clinically immune adults, showing that antibodies targeting asexual blood-stage antigens are an important component of protective immunity acquired following natural exposure to P. falciparum parasites (Cohen, McGregor and Carrington, Reference Cohen, McGregor and Carrington1961; McGregor, Carrington and Cohen, Reference McGregor, Carrington and Cohen1963; Sabchareon et al. Reference Sabchareon, Burnouf, Ouattara, Attanath, Bouharoun, Chantavanich, Foucault, Chongsuphajaisiddhi and Druilhe1991). Trans-placental transfer of IgG also seems to be responsible for resistance to malaria for the first months of life in infants born to clinically immune mothers (Bruce-Chwatt, Reference Bruce-Chwatt1952). Antibodies with specificity for a number of antigens expressed by asexual blood-stage parasites are likely to contribute to this protection. However, parasite-encoded, clonally variant surface antigens (VSA) expressed on the surface of the infected erythrocytes (IEs) appear to be of particular importance (Marsh et al. Reference Marsh, Otoo, Hayes, Carson and Greenwood1989), and the intra- and inter-clonal diversity of VSA go a long way towards explaining the sluggish acquisition of immunological protection (reviewed by Hviid, Reference Hviid2005). The general rule of P. falciparum malaria as a childhood disease in areas of intense parasite transmission has one important exception that has attracted substantial attention in recent years: pregnancy-associated malaria (PAM).

PREGNANCY-ASSOCIATED MALARIA

It is a long-recognized fact that pregnant women are at increased risk of malaria, with adverse maternal and foetal consequences (reviewed by Duffy and Desowitz, Reference Duffy, Desowitz, Duffy and Fried2001). This pregnancy-related susceptibility is apparent despite previously acquired protective immunity, and even in malaria-endemic areas, P. falciparum infection is therefore both more prevalent and more severe in pregnant women than in their non-pregnant peers (Walton, Reference Walton1949). It has often been speculated that PAM is an unavoidable consequence of maternal immuno-suppression or -modulation to protect the foetal allograft from rejection (Menendez, Reference Menendez1995). However, pregnancy-induced immune modulation mainly affects the cellular arm of immunity, whereas humoral immunity (upon which protection from malaria hinges) is largely unaffected (reviewed by Guilbert, Abbasi and Mosmann, Reference Guilbert, Abbasi, Mosmann, Duffy and Fried2001). Furthermore, susceptibility to PAM is concentrated among women of low parity, in particular primigravidae (McGregor, Reference McGregor1984). This suggests that susceptibility to PAM is due to a specific absence of immunity to a particular form or subset of P. falciparum parasites that can only infect pregnant women, and that protection against PAM-specific parasites is acquired following exposure to them during pregnancy in a manner similar to acquisition of protection from malaria in general. The hypothesis of a pregnancy-specific subset of P. falciparum is further supported by the facts that PAM is characterized by a selective accumulation of IEs in the placenta (Blacklock and Gordon, Reference Blacklock and Gordon1925) and that pregnancy-associated parasitaemia generally resolves spontaneously shortly after expulsion of the placenta at delivery (Nguyen-Dinh et al. Reference Nguyen-Dinh, Steketee, Greenberg, Wirima, Mulenda and Williams1988).

PAM is caused by functionally and immunologically unique parasites

Erythrocytes infected by mature (trophozoite and schizont) stages of P. falciparum parasites can bind to a range of different receptors in the host vasculature. The first adhesion receptor identified was CD36 (Barnwell, Ockenhouse and Knowles, Reference Barnwell, Ockenhouse and Knowles1985; Ockenhouse et al. Reference Ockenhouse, Tandon, Magowan, Jamieson and Chulay1989), followed by a range of other molecules, including the proteoglycan chondroitin sulphate A (CSA) (Robert et al. Reference Robert, Pouvelle, Meyer, Muanza, Fujioka, Aikawa, Scherf and Gysin1995; Rogerson et al. Reference Rogerson, Chaiyaroj, Ng, Reeder and Brown1995). The first direct piece of evidence in favour of the hypothesis of a discrete parasite subset being responsible for PAM was the finding that IEs isolated from the placenta of women with PAM exclusively bind to CSA, a receptor that is rarely – if ever – exploited as an adhesion receptor by P. falciparum-IEs in non-PAM infections (Fried and Duffy, Reference Fried and Duffy1996). This key observation was followed by the similarly important observation that placental and CSA-adhering IEs are not only functionally but also immunologically distinct from all other IEs (Fried et al. Reference Fried, Nosten, Brockman, Brabin and Duffy1998; Beeson et al. Reference Beeson, Brown, Molyneux, Mhango, Dzinjalamala and Rogerson1999; Ricke et al. Reference Ricke, Staalsoe, Koram, Akanmori, Riley, Theander and Hviid2000). As adhesion of IEs in general is mediated by VSA, these findings together pointed to a functionally and immunologically distinct subset of VSA that is exclusively expressed by placental and CSA-adhering parasites; a subset often referred to as VSAPAM.

Protective immunity to PAM is mediated by IgG with specificity for PAM-specific VSA

It is generally suspected that protective immunity to malaria depends on VSA-specific IgG that can interfere with receptor-specific IE adhesion (David et al. Reference David, Hommel, Miller, Udeinya and Oligino1983; Udeinya et al. Reference Udeinya, Miller, McGregor and Jensen1983), and that the piecemeal acquisition of protective immunity to malaria reflects the need to acquire a broad repertoire of such antibodies with specificity for a multitude of antigenically distinct VSA (Marsh and Howard, Reference Marsh and Howard1986; Bull et al. Reference Bull, Lowe, Kortok, Molyneux, Newbold and Marsh1998). The importance of VSAPAM in protective immunity against PAM was therefore reinforced when it was shown that serum antibodies can inhibit adhesion of IEs to CSA in a parity-dependent manner (Fried et al. Reference Fried, Nosten, Brockman, Brabin and Duffy1998; Ricke et al. Reference Ricke, Staalsoe, Koram, Akanmori, Riley, Theander and Hviid2000). In addition to inhibition of IE adhesion, opsonization and phagocytosis of IEs may also play an important role in protective immunity to PAM. The dominance of cytophilic subclasses among VSAPAM-specific IgG (Elliott et al. Reference Elliott, Brennan, Beeson, Tadesse, Molyneux, Brown and Rogerson2005; Megnekou et al. Reference Megnekou, Staalsoe, Taylor, Leke and Hviid2005) and the finding of impaired opsonization of VSAPAM-expressing IEs in HIV-infected women (Mount et al. Reference Mount, Mwapasa, Elliott, Beeson, Tadesse, Lema, Molyneux, Meshnick and Rogerson2004; Keen et al. Reference Keen, Serghides, Ayi, Patel, Ayisi, van Eijk, Steketee, Udhayakumar and Kain2007) support this possibility. In any case, levels of VSAPAM-specific IgG at delivery correlate inversely with placental parasitaemia (Staalsoe et al. Reference Staalsoe, Megnekou, Fievet, Ricke, Zornig, Leke, Taylor, Deloron and Hviid2001), and direct and compelling evidence of the clinical importance of CSA adhesion-inhibitory as well as VSAPAM-specific IgG have recently become available (Duffy and Fried, Reference Duffy and Fried2003; Staalsoe et al. Reference Staalsoe, Shulman, Bulmer, Kawuondo, Marsh and Hviid2004).

Molecular identification of VSAPAM

Most efforts to identify VSAPAM in molecular terms have focused on the best-described family of VSA, P. falciparum erythrocyte membrane protein 1 (PfEMP1) (Leech et al. Reference Leech, Barnwell, Miller and Howard1984). These high-molecular weight antigens are encoded by the var multi-gene family (Baruch et al. Reference Baruch, Pasloske, Singh, Bi, Ma, Feldman, Taraschi and Howard1995; Smith et al. Reference Smith, Chitnis, Craig, Roberts, Hudson-Taylor, Peterson, Pinches, Newbold and Miller1995; Su et al. Reference Su, Heatwole, Wertheimer, Guinet, Herrfeldt, Peterson, Ravetch and Wellems1995). Scherf et al. (Reference Scherf, Hernandez-Rivas, Buffet, Bottius, Benatar, Pouvelle, Gysin and Lanzer1998) observed transcription of a particular var gene, dubbed var CSA, in P. falciparum FCR3 selected for IE adhesion to CSA, and the Duffy-binding-like (DBL) 3-γ domain of the encoded PfEMP1 variant was found to have affinity for CSA (Buffet et al. Reference Buffet, Gamain, Scheidig, Baruch, Smith, Hernandez-Rivas, Pouvelle, Oishi, Fujii, Fusai, Parzy, Miller, Gysin and Scherf1999). Most P. falciparum genomes contain a var gene very similar to var CSA, and these related genes were grouped together in the var1csa sub-family of var genes (Rowe et al. Reference Rowe, Kyes, Rogerson, Babiker and Raza2002; Salanti et al. Reference Salanti, Jensen, Zornig, Staalsoe, Joergensen, Nielsen, Khattab, Arnot, Klinkert, Hviid and Theander2002). These findings, and the observation that var1csa is often highly transcribed by placental parasites (Fried and Duffy, Reference Fried and Duffy2002), fitted the earlier prediction (Fried et al. Reference Fried, Nosten, Brockman, Brabin and Duffy1998) that the antigen mediating IE adhesion to CSA, and the suspected target of PAM-specific immunity, was conserved between parasite clones. However, a number of other findings do not support the hypothesis of VAR1CSA as a PAM-type VSA, or its involvement as a target of protective immunity against PAM. Thus, high transcription of var1csa is not restricted to placental and CSA-adhering parasites (Rowe et al. Reference Rowe, Kyes, Rogerson, Babiker and Raza2002; Kyes et al. Reference Kyes, Christodoulou, Raza, Horrocks, Pinches, Rowe and Newbold2003), and levels of VAR1CSA-specific IgG do not correlate with gender or parity, in contrast to expectation regarding VSAPAM-specific IgG (Jensen et al. Reference Jensen, Zornig, Buhmann, Salanti, Koram, Riley, Theander, Hviid and Staalsoe2003). Finally, the ability of IEs to adhere to CSA is maintained after disruption of var1csa (Andrews et al. Reference Andrews, Pirrit, Przyborski, Sanchez, Sterkers, Ricken, Wickert, Lepolard, Avril, Scherf, Gysin and Lanzer2003).

An unusually structured gene, var2csa, is selectively transcribed by CSA-adhering and placental parasites

The availability of the complete P. falciparum genome (Gardner et al. Reference Gardner, Hall, Fung, White, Berriman, Hyman, Carlton, Pain, Nelson, Bowman, Paulsen, James, Eisen, Rutherford, Salzberg, Craig, Kyes, Chan, Nene, Shallom, Suh, Peterson, Angiuoli, Pertea, Allen, Selengut, Haft, Mather, Vaidya, Martin, Fairlamb, Fraunholz, Roos, Ralph, McFadden, Cummings, Subramanian, Mungall, Venter, Carucci, Hoffman, Newbold, Davis, Fraser and Barrell2002) opened the possibility of more precise analysis of var gene transcription than had previously been possible with degenerate primers (Taylor et al. Reference Taylor, Kyes, Harris, Kriek and Newbold2000). Taking this approach, Salanti et al. (Reference Salanti, Staalsoe, Lavstsen, Jensen, Sowa, Arnot, Hviid and Theander2003) analyzed changes in var gene transcription in response to selection of NF54-IEs for adhesion to CSA, which resulted in acquisition of the VSAPAM-type gender-specific and parity-dependent IgG recognition pattern of selected IEs (Ricke et al. Reference Ricke, Staalsoe, Koram, Akanmori, Riley, Theander and Hviid2000). The striking result was that the selection resulted in markedly increased and dominant transcription of a single, distinctly structured, var gene, PFL0030c (Salanti et al. Reference Salanti, Staalsoe, Lavstsen, Jensen, Sowa, Arnot, Hviid and Theander2003). PFE1640w, which belongs to the var1csa sub-family previously implicated in adhesion of IE to CSA, is a pseudo-gene in NF54/3D7, but data from other parasite lines have shown that selection for IE adhesion to CSA does not increase the abundance of var1csa transcripts (Salanti et al. Reference Salanti, Staalsoe, Lavstsen, Jensen, Sowa, Arnot, Hviid and Theander2003). Genes with high similarity to PFL0030c, and now grouped in the var2csa sub-family, appear to be present in all P. falciparum clones and to be selectively transcribed by CSA-selected and placental parasites alike (Salanti et al. Reference Salanti, Staalsoe, Lavstsen, Jensen, Sowa, Arnot, Hviid and Theander2003; Duffy et al. Reference Duffy, Byrne, Elliott, Wilson, Rogerson, Beeson, Noviyanti and Brown2005; Tuikue Ndam et al. Reference Tuikue Ndam, Salanti, Bertin, Dahlbäck, Fievet, Turner, Gaye, Theander and Deloron2005). The findings that several VAR2CSA domains have affinity for CSA (Gamain et al. Reference Gamain, Trimnell, Scheidig, Scherf, Miller and Smith2005) and that disruption of var2csa interferes with the ability to acquire the CSA-adhering phenotype further supports the PAM-relevance of this sub-family (Viebig et al. Reference Viebig, Gamain, Scheidig, Lepolard, Przyborski, Lanzer, Gysin and Scherf2005; Duffy et al. Reference Duffy, Maier, Byrne, Marty, Elliott, O'Neill, Payne, Rogerson, Cowman, Crabb and Brown2006). It is noteworthy that the var2csa response to CSA-selection had gone unnoticed in earlier studies because they used degenerate primers targeting DBL1-α or DBL1-γ encoding sequences (Taylor et al. Reference Taylor, Kyes, Harris, Kriek and Newbold2000; Fried and Duffy, Reference Fried and Duffy2002); domains that are not present in VAR2CSA.

VAR2CSA has the characteristics expected of VSAPAM

The distinct structure of var2csa compared to other var genes corresponded well with the expected functional and antigenic uniqueness of the PAM-type VSA it was assumed to encode (Lavstsen et al. Reference Lavstsen, Salanti, Jensen, Arnot and Theander2003; Kraemer and Smith, Reference Kraemer and Smith2003). Indeed, analysis of levels of VAR2CSA-specific IgG in P. falciparum-exposed adults confirmed the female-restricted and parity-dependent pattern expected of VSAPAM (Salanti et al. Reference Salanti, Dahlbäck, Turner, Nielsen, Barfod, Magistrado, Jensen, Lavstsen, Ofori, Marsh, Hviid and Theander2004). Importantly, VAR2CSA is present on the surface of intact VSAPAM-type IEs and absent from the surface of IEs that do not have this phenotype (Salanti et al. Reference Salanti, Dahlbäck, Turner, Nielsen, Barfod, Magistrado, Jensen, Lavstsen, Ofori, Marsh, Hviid and Theander2004; Barfod et al. Reference Barfod, Bernasconi, Dahlbäck, Jarrosay, Andersen, Salanti, Ofori, Turner, Resende, Nielsen, Theander, Sallusto, Lanzavecchia and Hviid2007). Finally, we have shown that high plasma levels of VAR2CSA-specific IgG correlate with protection from adverse clinical consequences of PAM (Salanti et al. Reference Salanti, Dahlbäck, Turner, Nielsen, Barfod, Magistrado, Jensen, Lavstsen, Ofori, Marsh, Hviid and Theander2004).

VAR2CSA appears to be the dominant target of the protective immune response to PAM

The importance of VSA-specific IgG relative to IgG with other antigen specificities for clinical protection against P. falciparum malaria is unknown, but may be high (Marsh et al. Reference Marsh, Otoo, Hayes, Carson and Greenwood1989). A parallel issue is the importance of IgG with specificity for VAR2CSA relative to other VSAPAM specificities in protection against PAM. To address this latter question, we cloned memory B cells from recently pregnant, P. falciparum-exposed multigravidae, using a recently developed and highly efficient immortalization method (Traggiai et al. Reference Traggiai, Becker, Subbarao, Kolesnikova, Uematsu, Gismondo, Murphy, Rappuoli and Lanzavecchia2004). The clones were subsequently screened for production of VSAPAM-specific monoclonal IgG using a panel of IEs displaying the VSAPAM phenotype. All except one of the eight VSAPAM-specific monoclonals had specificity for either the DBL3-X or the DBL5-ε domain of VAR2CSA (Barfod et al. Reference Barfod, Bernasconi, Dahlbäck, Jarrosay, Andersen, Salanti, Ofori, Turner, Resende, Nielsen, Theander, Sallusto, Lanzavecchia and Hviid2007). The characteristics of the remaining antibody suggest that it is also VAR2CSA-specific. Although var2csa is composed of alternating stretches of substantial and restricted interclonal diversity (Salanti et al. Reference Salanti, Staalsoe, Lavstsen, Jensen, Sowa, Arnot, Hviid and Theander2003; Dahlbäck et al. Reference Dahlbäck, Rask, Andersen, Nielsen, Tuikue-Ndam, Resende, Turner, Deloron, Hviid, Lund, Pedersen, Theander and Salanti2006; Trimnell et al. Reference Trimnell, Kraemer, Mukherjee, Phippard, Janes, Flamoe, Su, Awadalla and Smith2006), all the human monoclonal IgG antibodies targeted polymorphic rather than conserved epitopes (Barfod et al. Reference Barfod, Bernasconi, Dahlbäck, Jarrosay, Andersen, Salanti, Ofori, Turner, Resende, Nielsen, Theander, Sallusto, Lanzavecchia and Hviid2007). This finding suggests that domains of IE surface-expressed VAR2CSA that are accessible to protective antibodies are under selection pressure that favours polymorphism, in agreement with conclusions drawn from in silico analysis of var2csa (Dahlbäck et al. Reference Dahlbäck, Rask, Andersen, Nielsen, Tuikue-Ndam, Resende, Turner, Deloron, Hviid, Lund, Pedersen, Theander and Salanti2006; Trimnell et al. Reference Trimnell, Kraemer, Mukherjee, Phippard, Janes, Flamoe, Su, Awadalla and Smith2006). This pressure is most likely due to protective host immunity, supporting the clinical significance of the VAR2CSA-specific IgG response to PAM.

CONCLUDING REMARKS

VAR1CSA (as well as several non-PfEMP1 antigens) continues to be implicated in the pathogenesis as well as in the protective immune response to pregnancy-specific P. falciparum infection (Chia et al. Reference Chia, Badaut, Tuikue Ndam, Khattab, Igonet, Fievet, Bentley, Deloron and Klinkert2005; Badaut et al. Reference Badaut, Faure, Tuikue Ndam, Bertin, Chaffotte, Khattab, Klinkert, Deloron and Bentley2007), and is being explored as a candidate for development of vaccines against PAM (Gamain et al. Reference Gamain, Smith, Avril, Baruch, Scherf, Gysin and Miller2004; Chia et al. Reference Chia, Badaut, Tuikue Ndam, Khattab, Igonet, Fievet, Bentley, Deloron and Klinkert2005; Bir et al. Reference Bir, Yazdani, Avril, Layez, Gysin and Chitnis2006). However, from our perspective the bulk of current evidence identifies VAR2CSA as the main antigen mediating placental sequestration of P. falciparum-IEs and as the dominant and clinically most relevant target of the human IgG response to placental P. falciparum infection.

ACKNOWLEDGEMENTS

The PAM-specific research at Centre for Medical Parasitology receives financial support from the Bill and Melinda Gates Foundation, the Commission of the European Communities, the European Malaria Vaccine Initiative, the Danish Medical Research Council, and the Danish Research Council for Development Research.

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