Bassi Maria Rosaria, Cristinoi Bogdan, Buitenwerf Frank, Cuadrado Mark Bergholt, Björnsson Kasper Haldrup, Walker Melanie Rose, Partey Frederica Dedo, Ward Andrew B, Ofori Michael Fokuo, Barfod Lea
Centre for Translational Medicine and Parasitology at Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana.
PLoS Pathog. 2025 Apr 28;21(4):e1013107. doi: 10.1371/journal.ppat.1013107. eCollection 2025 Apr.
Plasmodium falciparum is responsible for the majority of malaria cases and deaths worldwide. In malaria endemic areas, natural immunity to blood stage infection is acquired over several exposures to the parasite and is thought to rely on antibodies. Antibodies can protect from severe disease through different effector functions, with complement activation lately emerging as an important feature of protective humoral responses to malaria. Plasmodium parasites have however evolved several mechanisms to evade complement attack, including the recruitment of complement down-regulatory proteins like Factor H (FH) and C1 esterase inhibitor (C1-INH). In this study, we report that merozoite-specific antibodies acquired naturally after infection activate the complement cascade in an exposure-dependent manner. Using plasma samples from convalescent children and exposed adults collected respectively in Hohoe and Accra (Ghana), we show that the ability to fix C1q and activate the classical pathway is similar for antibodies deriving from the two donors groups. However, downstream complement activation shown as deposition of the membrane attack complex (MAC) is strikingly higher with antibodies from children compared to antibodies from adults. Moreover, we demonstrate that antibodies from naturally exposed children can interfere with the merozoite recruitment of FH, but not of C1-INH. With the aim of neutralizing parasite evasion of the complement classical pathway, we develop a murine monoclonal antibody targeting PfMSP3, the binding partner of C1-INH on the merozoite surface. We demonstrate that this antibody can effectively block the binding of C1-INH to the parasite surface, unlike the naturally acquired ones. Using cryogenic electron microscopy, we obtain a low-resolution structure of the monoclonal antibody in complex with PfMSP3, which is the first reported structural data for this antigen. We propose targeting parasite antigens binding to complement down-regulators, together with leading vaccine candidate antigens, as a novel strategy to enhance the efficacy of future malaria vaccines.
恶性疟原虫是全球大多数疟疾病例和死亡的罪魁祸首。在疟疾流行地区，人们通过多次接触疟原虫获得对血液阶段感染的自然免疫力，这种免疫力被认为依赖于抗体。抗体可通过不同的效应功能预防重症疾病，补体激活近来已成为疟疾保护性体液反应的一个重要特征。然而，疟原虫已经进化出多种机制来逃避补体攻击，包括招募补体下调蛋白，如H因子（FH）和C1酯酶抑制剂（C1-INH）。在本研究中，我们报告感染后自然获得的裂殖子特异性抗体以暴露依赖的方式激活补体级联反应。使用分别在加纳霍霍埃和阿克拉收集的康复儿童和暴露成人的血浆样本，我们发现来自这两个供体组的抗体固定C1q并激活经典途径的能力相似。然而，作为膜攻击复合物（MAC）沉积表现出的下游补体激活，儿童抗体相比成人抗体显著更高。此外，我们证明自然暴露儿童的抗体可干扰裂殖子对FH的招募，但不能干扰对C1-INH的招募。为了中和疟原虫对补体经典途径的逃避，我们开发了一种靶向PfMSP3的鼠单克隆抗体，PfMSP3是裂殖子表面C1-INH的结合伙伴。我们证明，与自然获得的抗体不同，这种抗体可有效阻断C1-INH与寄生虫表面的结合。使用低温电子显微镜，我们获得了与PfMSP3复合的单克隆抗体的低分辨率结构，这是该抗原首次报道的结构数据。我们提出，将靶向与补体下调因子结合的寄生虫抗原与主要的疫苗候选抗原一起作为一种新策略，以提高未来疟疾疫苗的效力。
