Reduced risk of placental parasitemia associated with complement fixation on Plasmodium falciparum by antibodies among pregnant women

D Herbert Opi,Jo-Anne Chan,James G Beeson,Alice Ura,Ivo Mueller,Stephen J Rogerson,Alistair R D Mclean,Linda Reiling,Michelle J Boyle,Danielle I Stanisic,Freya J I Fowkes

doi:10.1186/s12916-021-02061-x

Abstract

BackgroundThe pathogenesis of malaria in pregnancy (MiP) involves accumulation of P. falciparum-infected red blood cells (pRBCs) in the placenta, contributing to poor pregnancy outcomes. Parasite accumulation is primarily mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1). Magnitude of IgG to pRBCs has been associated with reduced risk of MiP in some studies, but associations have been inconsistent. Further, antibody effector mechanisms are poorly understood, and the role of antibody complement interactions is unknown.MethodsStudying a longitudinal cohort of pregnant women (n=302) from a malaria-endemic province in Papua New Guinea (PNG), we measured the ability of antibodies to fix and activate complement using placental binding pRBCs and PfEMP1 recombinant domains. We determined antibody-mediated complement inhibition of pRBC binding to the placental receptor, chondroitin sulfate A (CSA), and associations with protection against placental parasitemia.ResultsSome women acquired antibodies that effectively promoted complement fixation on placental-binding pRBCs. Complement fixation correlated with IgG1 and IgG3 antibodies, which dominated the response. There was, however, limited evidence for membrane attack complex activity or pRBC lysis or killing. Importantly, a higher magnitude of complement fixing antibodies was prospectively associated with reduced odds of placental infection at delivery. Using genetically modified P. falciparum and recombinant PfEMP1 domains, we found that complement-fixing antibodies primarily targeted a specific variant of PfEMP1 (known as VAR2CSA). Furthermore, complement enhanced the ability of antibodies to inhibit pRBC binding to CSA, which was primarily mediated by complement C1q protein.ConclusionsThese findings provide new insights into mechanisms mediating immunity to MiP and reveal potential new strategies for developing malaria vaccines that harness antibody-complement interactions.

Highlights

The pathogenesis of malaria in pregnancy (MiP) involves accumulation of P. falciparum-infected red blood cells in the placenta, contributing to poor pregnancy outcomes
Antibodies from pregnant women promote complement fixation on placental binding P. falciparum-infected red blood cells (pRBCs) We tested whether acquired antibodies from pregnant women from a malaria endemic Papua New Guinea (PNG) region could fix and activate complement on pRBCs
Trophozoite stage pRBCs of the placental binding P. falciparum isolate CS2 were opsonized with antibodies from 302 PNG women or 15 malaria non-exposed Australian donors and tested for their ability to fix complement factors C1q or C3 by flow cytometry

Summary

Introduction

The pathogenesis of malaria in pregnancy (MiP) involves accumulation of P. falciparum-infected red blood cells (pRBCs) in the placenta, contributing to poor pregnancy outcomes. Parasite accumulation in the placenta is a key feature of MiP following infection with Plasmodium falciparum [2, 3] but is not prominent with other human infecting Plasmodium species This largely results from the selective binding of pRBCs to chondroitin sulfate A (CSA) expressed on syncytiotrophoblasts [4, 5], and other binding interactions may play secondary roles [6, 7]. This is mediated by a Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variant surface antigen, VAR2CSA, encoded by the var multigene family [5, 8]. VAR2CSA is a leading vaccine candidate for MiP with two VAR2CSA-based vaccines having completed phase I trials [13, 14], which highlights the importance of a strong understanding of immunity to inform further vaccine design and development for MiP

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