Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Malaria Research and Training Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali.
Commun Biol. 2021 Nov 19;4(1):1309. doi: 10.1038/s42003-021-02787-7.
Plasmodium falciparum-infected erythrocytes (IE) sequester in the placenta via surface protein VAR2CSA, which binds chondroitin sulfate A (CSA) expressed on the syncytiotrophoblast surface, causing placental malaria (PM) and severe adverse outcomes in mothers and their offspring. VAR2CSA belongs to the PfEMP1 variant surface antigen family; PfEMP1 proteins mediate IE adhesion and facilitate parasite immunoevasion through antigenic variation. Here we produced deglycosylated (native-like) and glycosylated versions of seven recombinant full-length VAR2CSA ectodomains and compared them for antigenicity and adhesiveness. All VAR2CSA recombinants bound CSA with nanomolar affinity, and plasma from Malian pregnant women demonstrated antigen-specific reactivity that increased with gravidity and trimester. However, allelic and glycosylation variants differed in their affinity to CSA and their serum reactivities. Deglycosylated proteins (native-like) showed higher CSA affinity than glycosylated proteins for all variants except NF54. Further, the gravidity-related increase in serum VAR2CSA reactivity (correlates with acquisition of protective immunity) was absent with the deglycosylated form of atypical M200101 VAR2CSA with an extended C-terminal region. Our findings indicate significant inter-allelic differences in adhesion and seroreactivity that may contribute to the heterogeneity of clinical presentations, which could have implications for vaccine design.
恶性疟原虫感染的红细胞（IE）通过表面蛋白 VAR2CSA 与合体滋养层表面表达的硫酸软骨素 A（CSA）结合而在胎盘内隐匿，导致胎盘疟疾（PM）和母亲及其后代的严重不良后果。VAR2CSA 属于 PfEMP1 变体表面抗原家族；PfEMP1 蛋白通过抗原变异介导 IE 黏附和寄生虫免疫逃避。在这里，我们制备了七个重组全长 VAR2CSA 胞外结构域的去糖基化（天然样）和糖基化版本，并比较了它们的抗原性和黏附性。所有 VAR2CSA 重组蛋白均以纳摩尔亲和力结合 CSA，来自马里孕妇的血浆显示出抗原特异性反应性，随着孕次和孕龄的增加而增加。然而，等位基因和糖基化变体在 CSA 的亲和力和血清反应性方面存在差异。与糖基化蛋白相比，除 NF54 外，所有变体的去糖基化蛋白（天然样）对 CSA 的亲和力更高。此外，与获得保护性免疫相关的血清 VAR2CSA 反应性（与获得保护性免疫相关）在具有延长 C 末端区域的非典型 M200101 VAR2CSA 的去糖基化形式中不存在。我们的研究结果表明，在黏附和血清反应性方面存在显著的等位基因差异，这可能导致临床表现的异质性，这可能对疫苗设计产生影响。
