Invited reviewPregnancy-associated malaria: Parasite binding, natural immunity and vaccine development
Introduction
The clinical impact of pregnancy-associated malaria (PAM) was first described 70 years ago and since then has been the subject of more than 2000 scientific papers (for review, see Brabin et al., 2004). Adverse outcomes include low birth weight babies, fetal loss, increased perinatal and maternal mortality, maternal anemia and the risk of hypertension in first-time pregnant mothers (Muehlenbachs et al., 2006). However, until recently it was not clear why high parasitemia occurred in pregnant women who otherwise possess significant clinical immunity to malaria. The basis for the accumulation of parasitised erythrocytes (PEs) in the placenta was unknown until it was shown that PEs from placenta bind to chondroitin sulfate A (CSA) and not to CD36, a common receptor for PE sequestration in the microvasculature (Fried and Duffy, 1996). This was the first direct evidence that a switch in parasite adhesion phenotype could regulate PE sequestration at different microvascular sites within the body and suggested that the placenta supports the clonal expansion of a unique subset of variants to which immunity has not yet developed.
Significantly, after one or two pregnancies transcendent antibodies that recognise placental PEs from different geographic regions develop and correlate with protection from malaria (Duffy and Fried, 2003, Fried et al., 1998, Staalsoe et al., 2004). Fried et al. (1998) were the first to show that antibodies against CSA-binding parasites are associated with maternal malaria resistance after multiple pregnancies and also block CSA-binding of placental isolates from different parts of the world, demonstrating the concept of a transcending immune response to the Plasmodium falciparum CSA ligand. These findings suggest that the surface molecule(s) expressed by placental variants have conserved antigenic determinants and have spurred efforts to characterise these protective antibodies and to induce them by vaccination. How and when natural PAM immunity develops is incompletely understood but will be important for designing a pregnancy malaria vaccine.
Section snippets
Pregnancy-associated malaria and natural protective immunity
Women develop increasing resistance to PAM infections over successive pregnancies (Brabin et al., 2004). This pattern of parity-specific resistance has been associated with the acquisition of antibodies to the surface of placental PEs (Beeson et al., 1999, Fried et al., 1998, Maubert et al., 1999, Ricke et al., 2000). Early in first pregnancies, women generally lack antibodies that react with the surface of placental binding PEs, which suggests these express novel surface variants. However, by
Parasite ligands mediating adhesion to CSA
The observation that maternal antibodies are broadly reactive to geographically diverse placental isolates underpins PAM vaccine efforts but also presents one of the central paradoxes for PAM immunity. Although this finding implies that placental isolates have shared epitopes, the only parasite antigens known to be at the PE surface at the time this observation was made were members of a highly diverse P. falciparum erythrocyte membrane protein 1 (PfEMP1) family encoded by var genes (Baruch et
Var1CSA and varCS2: two puzzling CSA binding var genes
In 1999, two var genes (FCR3varCSA and varCS2) were identified as being implicated in the CSA adhesion phenotype of the IT/FCR3 strain by two different groups (Buffet et al., 1999, Reeder et al., 1999). FCR3varCSA, also renamed var1CSA, encodes for a PfEMP1 protein that possesses eight receptor-like domains (seven DBL domains and one CIDR) (Fig. 2), whereas the varCS2 gene encodes for five domains (three DBL domains and two CIDR). By expressing recombinant proteins, it was shown that a DBLγ
Var2CSA: a predominant var gene expressed in placental isolates
At the time that researchers were trying to identify the var gene(s) involved in CSA adhesion, RT-PCR experiments were designed using degenerate primers based on the known DBL-α sequences present in the database (Peterson et al., 1995, Taylor et al., 2000). These primers were thought to cover most var genes, but with the release of the P. falciparum isolate 3D7 genome sequence, atypical var genes without DBL-α, or with highly divergent DBL-α, were identified. New primers specific for each var
Antigenic polymorphism in var2CSA
A central issue in pregnancy malaria vaccine development is to determine the specificity and antigenic diversity of epitopes targeted by protective maternal antibodies. While maternal antibodies are broadly reactive to placental isolates, it is not clear if placental isolates have highly conserved epitopes or if this cross-reactivity reflects different antibody specificities in the pool of antiserum. Indeed, recent serological comparisons suggest there is considerable antigenic polymorphism in
Intervention strategies against the CSA binding ligands
A promising avenue for new intervention strategies against PAM is to provide young women with the necessary immunity that would protect first time pregnant mothers and their fetuses against severe complications of placental infections. Either therapeutic antibodies or vaccination using recombinant var2CSA proteins are being considered. Before therapeutic antibodies can be provided to pregnant women, the potential risks to the fetus and mother, dosing schedule and approaches for monitoring the
Other receptors involved in PAM
While CSA is considered the major receptor for placental sequestration, the question arises whether other host receptors are responsible for PE binding to the syncytiotrophoblast layer or within the intervillous blood spaces where the majority of infected erythrocytes accumulate (Muthusamy et al., 2004). Two host receptors other than CSA have been postulated to play a role in placental sequestration: hyaluronic acid (HA) (Beeson et al., 2000) and neonatal Fc receptors via non-immune
Conclusion
Placental malaria is a classic example of malaria research that demonstrates the extraordinary benefit of bench work combined with field studies. The initial observation that laboratory parasites can bind to CSA helped frame the unique character of parasites isolated from the placenta. This observation has opened new avenues in the field of PAM and work on laboratory strains has been valuable in identifying the var gene that plays a key role in PAM. Conceptually, we are now moving closer to the
Acknowledgements
The authors are supported by a grant from the Bill & Melinda Gates Foundation (Grant No. 29202) as part of the Pregnancy Malaria vaccine consortium; A.S. and J.G. are supported by the BIOMALPAR program (LSHP-CT-2004-503578), an FP6-funded network of excellence; B.G. and J.G. are supported by a grant from the European Malaria Vaccine Initiative (Grant No. 01/2005); A.S. and J.G. are supported by a grant from the “Fonds dédié: Combattre les Maladies parasitaires” Sanofi Aventis – Ministère de la
References (92)
- et al.
Characterization of proteoglycans of human placenta and identification of unique chondroitin sulfate proteoglycans of the intervillous spaces that mediate the adherence of Plasmodium falciparum-infected erythrocytes to the placenta
J. Biol. Chem.
(2000) - et al.
Characterisation of anti-var2CSA-PfEMP1 cytoadhesion inhibitory mouse monoclonal antibodies
Microbes Infect.
(2006) - et al.
Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes
Cell
(1995) - et al.
Evaluating specific adhesion of Plasmodium falciparum-infected erythrocytes to immobilised hyaluronic acid with comparison to binding of mammalian cells
Int. J. Parasitol.
(2002) - et al.
The sick placenta – the role of malaria
Placenta
(2004) - et al.
VAR2CSA is the principal ligand for chondroitin sulfate A in two allogeneic isolates of Plasmodium falciparum
Mol. Biochem. Parasitol.
(2006) - et al.
Plasmodium falciparum: adhesion of placental isolates modulated by the sulfation characteristics of the glycosaminoglycan receptor
Exp. Parasitol.
(2000) - et al.
Plasmodium falciparum: chondroitin sulfate A is the major receptor for adhesion of parasitized erythrocytes in the placenta
Exp. Parasitol.
(2006) - et al.
Modifications in the CD36 binding domain of the Plasmodium falciparum variant antigen are responsible for the inability of chondroitin sulfate A adherent parasites to bind CD36
Blood
(2001) - et al.
Plasmodium falciparum: PCR detection and genotyping of isolates from peripheral, placental, and cord blood of pregnant Malawian women and their infants
Trans. R. Soc. Trop. Med. Hyg.
(2002)
A family affair: var genes, PfEMP1 binding, and malaria disease
Curr. Opin. Microbiol.
Sequestration of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A, a receptor for maternal malaria: monoclonal antibodies against the native parasite ligand reveal pan-reactive epitopes in placental isolates
Blood
Plasmodium falciparum-infected erythrocytes adhere both in the intervillous space and on the villous surface of human placenta by binding to the low-sulfated chondroitin sulfate proteoglycan receptor
Am. J. Pathol.
Chondroitin-4-sulphate (proteoglycan), a receptor for Plasmodium falciparum-infected erythrocyte adherence on brain microvascular endothelial cells
Res. Immunol.
A sub-family of common and highly conserved Plasmodium falciparum var genes
Mol. Biochem. Parasitol.
Identification of Plasmodium falciparum var1CSA and var2CSA domains that bind IgM natural antibodies
Mol. Biochem. Parasitol.
Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes
Cell
Decoding the language of var genes and Plasmodium falciparum sequestration
Trends Parasitol.
Variant surface antigen-specific IgG and protection against clinical consequences of pregnancy-associated Plasmodium falciparum malaria
Lancet
The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes
Cell
A study of var gene transcription in vitro using universal var gene primers
Mol. Biochem. Parasitol.
Global genetic diversity and evolution of var genes associated with placental and severe childhood malaria
Mol. Biochem. Parasitol.
Plasmodium falciparum cytoadherence to human placenta: evaluation of hyaluronic acid and chondroitin 4-sulfate for binding of infected erythrocytes
Exp. Parasitol.
Chondroitin sulfate proteoglycan expression and binding of Plasmodium falciparum-infected erythrocytes in the human placenta during pregnancy
Infect. Immun.
Recovery of adhesion to chondroitin-4-sulphate in Plasmodium falciparum varCSA disruption mutants by antigenically similar PfEMP1 variants
Mol. Microbiol.
Evolution of Plasmodium and the recent origin of the world populations of Plasmodium falciparum
Parasitologia
Baculovirus-expressed constructs induce immunoglobulin G that recognizes VAR2CSA on Plasmodium falciparum-infected erythrocytes
Infect. Immun.
Plasmodium falciparum isolates from infected pregnant women and children are associated with distinct adhesive and antigenic properties
J. Infect. Dis.
Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria
Nat. Med.
Selective accumulation of mature asexual stages of Plasmodium falciparum-infected erythrocytes in the placenta
Infect. Immun.
Plasmodium falciparum-infected erythrocytes demonstrate dual specificity for adhesion to hyaluronic acid and chondroitin sulfate A and have distinct adhesive properties
J. Infect. Dis.
Antibodies to variant surface antigens of Plasmodium falciparum-infected erythrocytes and adhesion inhibitory antibodies are associated with placental malaria and have overlapping and distinct targets
J. Infect. Dis.
Antigenic differences and conservation among placental Plasmodium falciparum-infected erythrocytes and acquisition of variant-specific and cross-reactive antibodies
J. Infect. Dis.
Intercellular adhesion molecule-1 is an endothelial cell adhesion receptor for Plasmodium falciparum
Nature
Immunogenicity of duffy binding-like domains that bind chondroitin sulfate A and protection against pregnancy-associated malaria
Infect. Immun.
An analysis of malaria in pregnancy in Africa
Bull. World Health Organ.
Plasmodium falciparum domain mediating adhesion to chondroitin sulfate A: a receptor for human placental infection
Proc. Natl. Acad. Sci. USA
Placental malaria. I. Pathological classification
Histopathology
Inhibition of adhesion of Plasmodium falciparum-infected erythrocytes by structurally defined hyaluronic acid dodecasaccharides
Infect. Immun.
Developmental selection of var gene expression in Plasmodium falciparum
Nature
Immunization with recombinant duffy binding-like-gamma3 induces pan-reactive and adhesion-blocking antibodies against placental chondroitin sulfate A-binding Plasmodium falciparum parasites
J. Infect. Dis.
Is malarial placental infection related to peripheral infection at any time of pregnancy?
Am. J. Trop. Med. Hyg.
Nonspecific immunoglobulin M binding and chondroitin sulfate A binding are linked phenotypes of Plasmodium falciparum isolates implicated in malaria during pregnancy
Infect. Immun.
In vivo transcriptome of Plasmodium falciparum reveals overexpression of transcripts that encode surface proteins
J. Infect. Dis.
Broad analysis reveals a consistent pattern of var gene transcription in Plasmodium falciparum repeatedly selected for a defined adhesion phenotype
Mol. Microbiol.
Transcribed var genes associated with placental malaria in Malawian women
Infect. Immun.
Cited by (0)
- 1
These authors contributed equally to the work.