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. 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. 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. 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.

中文翻译：

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孕妇抗体与恶性疟原虫补体结合相关的胎盘寄生虫血症风险降低

妊娠期疟疾 (MiP) 的发病机制涉及感染恶性疟原虫的红细胞 (pRBC) 在胎盘中的积累，从而导致妊娠结局不佳。寄生虫积累主要由恶性疟原虫红细胞膜蛋白 1 (PfEMP1) 介导。在一些研究中，针对 pRBC 的 IgG 水平与 MiP 风险降低相关，但相关性并不一致。此外，抗体效应机制知之甚少，抗体补体相互作用的作用尚不清楚。研究来自巴布亚新几内亚 (PNG) 疟疾流行省的孕妇 (n=302) 的纵向队列，我们​​使用胎盘结合 pRBC 和 PfEMP1 重组结构域测量了抗体固定和激活补体的能力。我们确定了抗体介导的补体抑制 pRBC 与胎盘受体、硫酸软骨素 A (CSA) 的结合，以及与胎盘寄生虫血症的保护作用。一些女性获得了有效促进胎盘结合 pRBC 上的补体固定的抗体。补体固定与 IgG1 和 IgG3 抗体相关，它们主导了反应。然而，膜攻击复合物活性或 pRBC 裂解或杀死的证据有限。重要的是，较高量级的补体固定抗体与分娩时胎盘感染的几率降低有关。使用转基因恶性疟原虫和重组 PfEMP1 域，我们发现补体固定抗体主要针对 PfEMP1 的特定变体（称为 VAR2CSA）。此外，补体增强了抗体抑制 pRBC 与 CSA 结合的能力，这主要由补体 C1q 蛋白介导。这些发现提供了对介导对 MiP 免疫的机制的新见解，并揭示了开发利用抗体-补体相互作用的疟疾疫苗的潜在新策略。