Cowman Alan, Seager Benjamin, Lim Pailene, Lai Keng-Heng, Feufack-Donfack Lionel, Dass Sheena, Xiao Xiao, Jung Nicolai, Abraham Anju, Grigg Matthew, Anstey Nicholas, William Timothy, Sattabongkot Jetsumon, Leis Andrew, Longley Rhea, Duraisingh Manoj, Popovici Jean, Wilson Danny, Scally Stephen
Walter and Eliza Hall Institute of Medical Research.
The Walter and Eliza Hall Institute of Medical Research.
Res Sq. 2025 Apr 28:rs.3.rs-6292540. doi: 10.21203/rs.3.rs-6292540/v1.
Invasion of erythrocytes by members of the Plasmodium genus is an essential step of the parasite lifecycle, orchestrated by numerous host-parasite interactions. In P. falciparum Rh5, with PfCyRPA, PfRipr, PfCSS, and PfPTRAMP, forms the essential PCRCR complex which binds basigin on the erythrocyte surface. Rh5 is restricted to P. falciparum and its close relatives; however, PTRAMP, CSS and Ripr orthologs are present across the Plasmodium genus. We investigated PTRAMP, CSS and Ripr orthologs from three species to elucidate common features of the complex. Like P. falciparum, PTRAMP and CSS form a disulfide-linked heterodimer in both P. vivax and P. knowlesi with all three species forming a complex (PCR) with Ripr by binding its C-terminal region. Cross-reactive antibodies targeting the PCR complex differentially inhibit merozoite invasion. Cryo-EM visualization of the P. knowlesi PCR complex confirmed predicted models and revealed a core invasion scaffold in Plasmodium spp. with implications for vaccines targeting multiple species of malaria-causing parasites.
疟原虫属成员对红细胞的入侵是寄生虫生命周期中的关键步骤，由众多宿主-寄生虫相互作用精心编排。在恶性疟原虫中，Rh5与PfCyRPA、PfRipr、PfCSS和PfPTRAMP形成必需的PCRCR复合物，该复合物与红细胞表面的基底膜结合。Rh5仅限于恶性疟原虫及其近亲；然而，PTRAMP、CSS和Ripr直系同源物存在于整个疟原虫属中。我们研究了来自三个物种的PTRAMP、CSS和Ripr直系同源物，以阐明该复合物的共同特征。与恶性疟原虫一样，PTRAMP和CSS在间日疟原虫和诺氏疟原虫中均形成二硫键连接的异二聚体，这三个物种均通过结合其C末端区域与Ripr形成复合物（PCR）。靶向PCR复合物的交叉反应抗体可不同程度地抑制裂殖子入侵。诺氏疟原虫PCR复合物的冷冻电镜可视化证实了预测模型，并揭示了疟原虫属中的核心入侵支架，这对靶向多种疟原虫的疫苗具有重要意义。
