Protective Antibodies against Placental Malaria and Poor Outcomes during Pregnancy, Benin - Volume 21, Number 5—May 2015 - Emerging Infectious Disease journal - CDC
Volume 21, Number 5—May 2015
Research
Protective Antibodies against Placental Malaria and Poor Outcomes during Pregnancy, Benin
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Nicaise Tuikue Ndam , Lise Denoeud-Ndam, Justin Doritchamou, Firmine Viwami, Ali Salanti, Morten A. Nielsen, Nadine Fievet, Achille Massougbodji, Adrian J.F. Luty, and Philippe Deloron
Abstract
Placental malaria is caused by Plasmodium falciparum–infected erythrocytes that bind to placental tissue. Binding is mediated by VAR2CSA, a parasite antigen coded by the var gene, which interacts with chondroitin sulfate A (CSA). Consequences include maternal anemia and fetal growth retardation. Antibody-mediated immunity to placental malaria is acquired during successive pregnancies, but the target of VAR2CSA-specific protective antibodies is unclear. We assessed VAR2CSA-specific antibodies in pregnant women and analyzed their relationships with protection against placental infection, preterm birth, and low birthweight. Antibody responses to the N-terminal region of VAR2CSA during early pregnancy were associated with reduced risks for infections and low birthweight. Among women infected during pregnancy, an increase in CSA binding inhibition was associated with reduced risks for placental infection, preterm birth, and low birthweight. These data suggest that antibodies against VAR2CSA N-terminal region mediate immunity to placental malaria and associated outcomes. Our results validate current vaccine development efforts with VAR2CSA N-terminal constructs.
Tissue sequestration of Plasmodium falciparum–infected erythrocytes drives malaria-related pathologic changes (1). Tissue sequestration is primarily mediated by members of the parasite variant antigen family of P. falciparumerythrocyte membrane protein 1, which is expressed on the membrane of infected erythrocytes. These proteins display extensive antigenic variation, concurrently changing receptor recognition, and tissue tropism of infected erythrocytes (2). Accumulation of infected erythrocytes in placental intervillous spaces characterizes malaria during pregnancy (3). This sequestration of infected erythrocytes results in maternal anemia and low birthweight (LBW) (4–6), as well as consequences for child health (7–10).
Sequestration of infected erythrocytes in the placenta is mediated by VAR2CSA, the P. falciparum erythrocyte membrane protein 1 variant that binds to chondroitin sulfate A (CSA) on the syncytiotrophoblast (11,12). VAR2CSA is a multidomain protein (≈350 kDa). Acquisition of antibodies against VAR2CSA occurs during pregnancy after exposure to infected erythrocytes sequestering in the placenta. Concentrations of these antibodies and those of antibodies that inhibit binding of infected erythrocytes to CSA (13,14) increase with parity. Furthermore, women with VAR2CSA-specific antibodies give birth to babies with higher birthweights (15). VAR2CSA-expressing parasites are the primary cause of placental malaria (16,17), which suggests that parasites can escape preexisting immunity (i.e., that naturally acquired immunity against preerythrocytic or erythrocytic stages of malaria does not protect against this syndrome).
The demonstration that parasites that have the var2csa knockout gene irreversibly lose the ability to adhere to CSA (18), as well as the ability of VAR2CSA to induce antibodies that inhibit adherence of placental infective erythrocytes to CSA in vitro, strongly argue for use of VAR2CSA as a vaccine against placental malaria. However, VAR2CSA-based vaccine research is challenged by the size and polymorphism of this protein and requires identification of smaller functional domains that combine an ability to induce strain-transcending antibody responses with a facility of production in a recombinant protein form. Therefore, identifying the region of VAR2CSA that induces antibodies associated with protection in multigravid women in malaria-endemic regions is a priority. The VAR2CSA critical CSA binding site is located in its N-terminal region (19–21), but the characteristics of naturally acquired antibodies against this region remain to be defined.
The Strategies to Prevent Pregnancy-associated Malaria Project, a cohort study of pregnant women enrolled early in pregnancy and followed up until delivery, was conducted during 2008–2011 in Comé in southern Benin. In this substudy, we assessed the effect of antibody response to placental infected erythrocytes, measured early in pregnancy and at delivery, on major pregnancy outcomes.
Dr. Tuikue Ndam is a senior research officer the Mother and Child Health in the Tropics Laboratory Branch of the Institut de Recherche pour le Développement, Paris, France. His research interests focus on using molecular and cell biology approaches to identify critical biological factors that control pathogenesis of P. falciparum infections.
Acknowledgments
We thank the women for participating in the study; the medical staffs of Akodeha, Come Central, and Ouedeme Pedah Health Centers for making valuable contributions; Thomas Clausen for producing FV2 recombinant protein; and Valérie Briand for providing ultrasound data.
This study was supported by the European 7th Framework Program (contract no. 200889 for the Small & Medium Scale Collaborative Project Strategies To Prevent Pregnancy-Associated Malaria). J. D. was supported by a PhD studentship from Agence Inter-établissements de Recherche pour le Dévelopement.
N.T.N., P.D., and A.J.F.L. conceived and designed the study; J.D., F.V., and N.T.N. conducted laboratory experiments; L.D.-N. and N.T.N. analyzed data; N.F., M.A.N., A.S., and A.M. provided reagents, materials, and analysis tools; J.D., L.D., A.J.F.L., P.D., and N.T.N drafted and finalized the manuscript.
References
- Miller LH, Baruch DI, Marsh K, Doumbo OK. The pathogenic basis of malaria. Nature. 2002;415:673–9. DOIPubMed
- Kraemer SM, Smith JD. A family affair: var genes, PfEMP1 binding, and malaria disease. Curr Opin Microbiol. 2006;9:374–80. DOIPubMed
- Muthusamy A, Achur RN, Bhavanandan VP, Fouda GG, Taylor DW, Gowda DC. 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. 2004;164:2013–25. DOIPubMed
- Brabin BJ, Romagosa C, Abdelgalil S, Menéndez C, Verhoeff FH, McGready R, The sick placenta-the role of malaria. Placenta. 2004;25:359–78.DOIPubMed
- Hartman TK, Rogerson SJ, Fischer PR. The impact of maternal malaria on newborns. Ann Trop Paediatr. 2010;30:271–82. DOIPubMed
- Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis.2007;7:93–104. DOIPubMed
- Le Hesran JY, Cot M, Personne P, Fievet N, Dubois B, Beyemé M, Maternal placental infection with Plasmodium falciparum and malaria morbidity during the first 2 years of life. Am J Epidemiol. 1997;146:826–31. DOIPubMed
- Bardají A, Sigauque B, Sanz S, Maixenchs M, Ordi J, Aponte JJ, Impact of malaria at the end of pregnancy on infant mortality and morbidity. J Infect Dis. 2011;203:691–9. DOIPubMed
- Schwarz NG, Adegnika AA, Breitling LP, Gabor J, Agnandji ST, Newman RD, Placental malaria increases malaria risk in the first 30 months of life. Clin Infect Dis. 2008;47:1017–25. DOIPubMed
- Black RE, Cousens S, Johnson HL, Lawn JE, Rudan I, Bassani DG, Child Health Epidemiology Reference Group of WHO and UNICEF: Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet. 2010;375:1969–87. DOIPubMed
- Khunrae P, Dahlbäck M, Nielsen MA, Andersen G, Ditlev SB, Resende M, Full-length recombinant Plasmodium falciparum VAR2CSA binds specifically to CSPG and induces potent parasite adhesion-blocking antibodies. J Mol Biol. 2010;397:826–34. DOIPubMed
- Srivastava A, Gangnard S, Round A, Dechavanne S, Juillerat A, Raynal B, Full-length extracellular region of the var2CSA variant of PfEMP1 is required for specific, high-affinity binding to CSA. Proc Natl Acad Sci U S A. 2010;107:4884–9. DOIPubMed
- Tuikue Ndam NG, Salanti A, Le-Hesran J-Y, Cottrell G, Fievet N, Turner L, Dynamics of anti-VAR2CSA immunoglobulin G response in a cohort of senegalese pregnant women. J Infect Dis. 2006;193:713–20. DOIPubMed
- O’Neil-Dunne I, Achur RN, Agbor-Enoh ST, Valiyaveettil M, Naik RS, Ockenhouse CF, Gravidity-dependent production of antibodies that inhibit binding of Plasmodium falciparum–infected erythrocytes to placental chondroitin sulfate proteoglycan during pregnancy. Infect Immun.2001;69:7487–92. DOIPubMed
- Salanti A, Dahlbäck M, Turner L, Nielsen MA, Barfod L, Magistrado P, Evidence for the involvement of VAR2CSA in pregnancy-associated malaria. J Exp Med. 2004;200:1197–203. DOIPubMed
- Tuikue Ndam NG, Salanti A, Bertin G, Dahlbäck M, Fievet N, Bertin G, High levels of var2csa transcription by Plasmodium falciparum isolated from the placenta. J Infect Dis. 2005;192:331–5. DOIPubMed
- Magistrado P, Salanti A, Tuikue Ndam NG, Mwakalinga SB, Resende M, Dahlbäck M, VAR2CSA expression on the surface of placenta-derivedPlasmodium falciparum–infected erythrocytes. J Infect Dis. 2008;198:1071–4. DOIPubMed
- Viebig NK, Gamain B, Scheidig C, Lépolard C, Przyborski J, Lanzer M, A single member of the Plasmodium falciparum var multigene family determines cytoadhesion to the placental receptor chondroitin sulphate A. EMBO Rep. 2005;6:775–81. DOIPubMed
- Bigey P, Gnidehou S, Doritchamou J, Quiviger M, Viwami F, Couturier A, The NTS-DBL2X region of VAR2CSA induces cross-reactive antibodies that inhibit adhesion of several Plasmodium falciparum isolates to chondroitin sulfate A. J Infect Dis. 2011;204:1125–33. DOIPubMed
- Dahlbäck M, Jørgensen LM, Nielsen MA, Clausen TM, Ditlev SB, Resende M, The chondroitin sulfate A-binding site of the VAR2CSA protein involves multiple N-terminal domains. J Biol Chem. 2011;286:15908–17. DOIPubMed
- Srivastava A, Gangnard S, Dechavanne S, Amirat F, Lewit Bentley A, Bentley GA, Var2CSA minimal CSA binding region is located within the N-terminal region. PLoS ONE. 2011;6:e20270. DOIPubMed
- Huynh B-T, Fievet N, Gbaguidi G, Dechavanne S, Borgella S, Guezo-Mevo B, Influence of the timing of malaria infection during pregnancy on birth weight and on maternal anemia in Benin. Am J Trop Med Hyg. 2011;85:214–20. DOIPubMed
- Schmiegelow C, Minja D, Oesterholt M, Pehrson C, Suhrs HE, Boström S, Malaria and fetal growth alterations in the 3(rd) trimester of pregnancy: a longitudinal ultrasound study. PLoS ONE. 8:e53794.
- Haase RN, Megnekou R, Lundquist M, Ofori MF, Hviid L, Staalsoe T. Plasmodium falciparum parasites expressing pregnancy-specific variant surface antigens adhere strongly to the choriocarcinoma cell line BeWo. Infect Immun. 2006;74:3035–8. DOIPubMed
- Staalsoe T, Giha HA, Dodoo D, Theander TG, Hviid L. Detection of antibodies to variant antigens on Plasmodium falciparum–infected erythrocytes by flow cytometry. Cytometry. 1999;35:329–36. DOIPubMed
- Tuikue Ndam NG, Fievet N, Bertin G, Gsaye A, Deloron P. Variable adhesion abilities and overlapping properties in placental Plasmodium falciparumisolates. J Infect Dis. 2004;190:2001–9. DOIPubMed
- Brolin KJ, Persson KE, Wahlgren M, Rogerson SJ, Chen Q. Differential recognition of P. falciparum VAR2CSA domains by naturally acquired antibodies in pregnant women from a malaria endemic area. PLoS ONE. 2010;5:e9230. DOIPubMed
- Fried M, Duffy PE. Analysis of CSA-binding parasites and antiadhesion antibodies. Methods Mol Med. 2002;72:555–60 .PubMed
- Nielsen MA, Pinto VV, Resende M, Dahlbäck M, Ditlev SB, Theander TG, Induction of adhesion-inhibitory antibodies against placental Plasmodium falciparum parasites by using single domains of VAR2CSA. Infect Immun. 2009;77:2482–7. DOIPubMed
- Guitard J, Cottrell G, Magnouha N, Salanti A, Li T, Sow S, Differential evolution of anti-VAR2CSA- IgG3 in primigravidae and multigravidae pregnant women infected by Plasmodium falciparum. Malar J. 2008;7:10. DOIPubMed
- Aickin M, Gensler H. Adjusting for multiple testing when reporting research results: the Bonferroni vs Holm methods. Am J Public Health.1996;86:726–8. DOIPubMed
- Duffy PE, Fried M. Antibodies that inhibit Plasmodium falciparum adhesion to chondroitin sulfate A are associated with increased birth weight and the gestational age of newborns. Infect Immun. 2003;71:6620–3. DOIPubMed
- Tutterrow YL, Avril M, Singh K, Long CA, Leke RJ, Sama G, High levels of antibodies to multiple domains and strains of VAR2CSA correlate with the absence of placental malaria in Cameroonian women living in an area of high Plasmodium falciparum transmission. Infect Immun. 2012;80:1479–90.DOIPubMed
- Doritchamou J, Bertin G, Moussiliou A, Bigey P, Viwami F, Ezinmegnon S, First-trimester Plasmodium falciparum infections display a typical “placental” phenotype. J Infect Dis. 2012;206:1911–9 . DOIPubMed
- Clausen TM, Christoffersen S, Dahlback M, Langkilde AE, Jensen KE, Resende M, Structural and functional insight into how the Plasmodium falciparum VAR2CSA protein mediates binding to chondroitin sulfate A in placental malaria. J Biol Chem. 2012;287:23332–45. DOIPubMed
- Bordbar B, Tuikue-Ndam N, Bigey P, Doritchamou J, Scherman D, Deloron P. Identification of Id1–DBL2X of VAR2CSA as a key domain inducing highly inhibitory and cross-reactive antibodies. Vaccine. 2012;30:1343–8. DOIPubMed
- Babakhanyan A, Leke RG, Salanti A, Bobbili N, Gwanmesia P, Leke RJ, The antibody response of pregnant Cameroonian women to VAR2CSA ID1–ID2a, a small recombinant protein containing the CSA-binding site. PLoS ONE. 2014;9:e88173. DOIPubMed
- Doritchamou J, Sossou-Tchatcha S, Cottrell G, Moussiliou A, Hounton Houngbeme C, Massougbodji A, Dynamics in the cytoadherence phenotypes of Plasmodium falciparum infected erythrocytes isolated during pregnancy. PLoS ONE. 2014;9:e98577. DOIPubMed
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Suggested citation for this article: Tuikue Ndam N, Denoeud-Ndam L, Doritchamou J, Viwami F, Salanti A, Nielsen MA, et al. Protective antibodies against placental malaria and poor outcomes during pregnancy, Benin. Emerg Infect Dis. 2015 May [date cited]. http://dx.doi.org/10.3201/eid2105.141626
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