Lopez-Perez Mary, Viwami Firmine, Ampomah Paulina, Šuštić Tonći, Larsen Mads Delbo, Wuhrer Manfred, Vidarsson Gestur, Ofori Michael F, Tuikue Ndam Nicaise, Hviid Lars
Centre for Translational Medicine and Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Institut de Recherche Clinique du Benin, Abomey Calavi, Benin.
J Infect Dis. 2024 Nov 25. doi: 10.1093/infdis/jiae529.
Acquired immunity to Plasmodium falciparum malaria is mainly mediated by immunoglobulin G (IgG) targeting erythrocyte membrane protein 1 (PfEMP1). These adhesins mediate infected erythrocyte (IE) sequestration, protecting IEs from splenic destruction. PfEMP1-specific IgG is therefore thought to protect mainly by inhibiting IE sequestration. VAR2CSA-type PfEMP1 mediates placental IE sequestration, putting pregnant women exposed to P falciparum parasites at risk of placental malaria (PM).
Levels and Fc-afucosylation of VAR2CSA-specific plasma IgG were measured by a modified enzyme-linked immunosorbent assay (FEASI). We also measured the ability of the IgG to inhibit IE adhesion and to induce natural killer (NK) cell degranulation. The results were related to parity and clinical pregnancy outcomes.
Parity was positively correlated with levels and Fc-afucosylation of VAR2CSA-specific IgG, and with birth weight and plasma IgG inhibition of IE adhesion in vitro. Fc-afucosylation of VAR2CSA-specific IgG increased NK-cell degranulation. Women with Fc-afucosylated VAR2CSA-specific IgG had a reduced risk of delivering a low birth weight (LBW) baby, but not of PM or anemia.
Fc-afucosylated VAR2CSA-specific IgG effectively induced NK-cell degranulation and was associated with protection against LBW, independent of IgG levels. Our study has implications for the development of VAR2CSA-based subunit vaccines, which exclusively induce Fc-fucosylated IgG.
对恶性疟原虫疟疾的获得性免疫主要由靶向红细胞膜蛋白1（PfEMP1）的免疫球蛋白G（IgG）介导。这些黏附素介导感染红细胞（IE）的滞留，保护IE免受脾脏破坏。因此，PfEMP1特异性IgG被认为主要通过抑制IE滞留来提供保护。VAR2CSA型PfEMP1介导胎盘IE滞留，使暴露于恶性疟原虫寄生虫的孕妇有患胎盘疟疾（PM）的风险。
通过改良酶联免疫吸附测定（FEASI）测量VAR2CSA特异性血浆IgG的水平和Fc-岩藻糖基化。我们还测量了IgG抑制IE黏附以及诱导自然杀伤（NK）细胞脱颗粒的能力。结果与产次和临床妊娠结局相关。
产次与VAR2CSA特异性IgG的水平和Fc-岩藻糖基化呈正相关，与出生体重以及体外血浆IgG对IE黏附的抑制作用呈正相关。VAR2CSA特异性IgG的Fc-岩藻糖基化增加了NK细胞的脱颗粒。具有Fc-岩藻糖基化VAR2CSA特异性IgG的女性分娩低出生体重（LBW）婴儿的风险降低，但患PM或贫血的风险未降低。
Fc-岩藻糖基化的VAR2CSA特异性IgG有效地诱导了NK细胞脱颗粒，并且与预防LBW相关，与IgG水平无关。我们的研究对基于VAR2CSA的亚单位疫苗的开发具有启示意义，该疫苗专门诱导Fc-岩藻糖基化的IgG。
