Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
Infect Immun. 2018 Oct 25;86(11). doi: 10.1128/IAI.00435-18. Print 2018 Nov.
malaria pathogenesis is tied to the sequestration of parasites in the microvasculature. Parasite sequestration leading to severe malaria is mediated by erythrocyte membrane protein 1 (PfEMP1) binding to endothelial protein C receptor (EPCR) via its CIDRα1 domains. CIDRα1 domains are targets of naturally acquired immunity, and a vaccine eliciting antibodies inhibiting the EPCR binding of CIDRα1 could potentially prevent disease and death from malaria. CIDRα1 domains have diversified in sequence to escape immune recognition but preserved structure to maintain EPCR binding. The EPCR-binding CIDRα1 domains separate into six major sequence types predicted to form a conserved structure in which only the amino acids essential for EPCR binding are highly conserved. Here, we investigated whether antibodies elicited by vaccination with single or multiple recombinant CIDRα1 domains are able to bind and inhibit diverse CIDRα1 domains. We found that EPCR binding-inhibitory antibodies to CIDRα1 variants closely related to those used for vaccination are readily elicited, whereas antibodies binding distant CIDRα1 variants are sporadically generated and are rarely inhibitory. Despite this, sequence similarity correlated poorly with the ability of induced antibodies to inhibit across diverse variants, and no continuous sequence regions of importance for cross-inhibitory antibodies could be identified. This suggested that epitopes of cross-variant inhibitory antibodies were predominantly conformational. Vaccination with immunogens engineered to focus immune responses to specific epitopes or an optimal choice of multiple CIDRα1 variants may improve elicitation of broadly reactive and inhibitory antibody responses.
疟原虫发病机制与寄生虫在微血管中的隔离有关。寄生虫隔离导致严重疟疾是通过红细胞膜蛋白 1（PfEMP1）通过其 CIDRα1 结构域与内皮蛋白 C 受体（EPCR）结合介导的。CIDRα1 结构域是天然获得性免疫的靶标，一种引发能够抑制 CIDRα1 与 EPCR 结合的抗体的疫苗，可能预防疟疾引起的疾病和死亡。CIDRα1 结构域在序列上已经多样化以逃避免疫识别，但保持结构以维持 EPCR 结合。EPCR 结合的 CIDRα1 结构域分为六个主要序列类型，预计形成一个保守结构，其中只有对 EPCR 结合至关重要的氨基酸高度保守。在这里，我们研究了接种单个或多个重组 CIDRα1 结构域疫苗后产生的抗体是否能够结合并抑制多种 CIDRα1 结构域。我们发现，对与用于疫苗接种的 CIDRα1 变体密切相关的 CIDRα1 变体产生的 EPCR 结合抑制性抗体很容易被诱导，而与遥远的 CIDRα1 变体结合的抗体则很少产生且很少具有抑制作用。尽管如此，诱导抗体的序列相似性与在多种变体上抑制的能力相关性很差，并且无法确定对交叉抑制性抗体重要的连续序列区域。这表明，交叉变体抑制性抗体的表位主要是构象性的。通过工程免疫原聚焦于特定表位的免疫反应或选择多个 CIDRα1 变体的最佳组合的疫苗接种，可能会改善广泛反应性和抑制性抗体反应的诱导。
