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

Opi, DH; Boyle, MJ; McLean, ARD; Reiling, L; Chan, JA; Stanisic, DI; Ura, A; Mueller, I; Fowkes, FJI; Rogerson, SJ; Beeson, JG

Author(s): Opi, DH; Boyle, MJ; McLean, ARD; Reiling, L; Chan, JA; Stanisic, DI; Ura, A; Mueller, I; Fowkes, FJI; Rogerson, SJ; Beeson, JG;
Details: Publication Year 2021-08-24,Volume 19,Issue #1,Page 201
Journal Title: BMC Medicine
Abstract: BACKGROUND: 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 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. METHODS: Studying 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. RESULTS: Some 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. CONCLUSIONS: These findings provide new insights into mechanisms mediating immunity to MiP and reveal potential new strategies for developing malaria vaccines that harness antibody-complement interactions.
Keywords: Antibodies; Complement; Malaria; Pregnancy; Var2csa
Research Division(s): Population Health And Immunity
PubMed ID: 34425801
Publisher's Version: https://doi.org/10.1186/s12916-021-02061-x
Open Access at Publisher's Site: https://doi.org/10.1186/s12916-021-02061-x
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Opi et al_BMC Medicine.pdf - (1.51MB, application/pdf)

Creation Date: 2021-09-17 11:04:13

Last Modified: 2021-09-17 11:20:29