Joof Fatou, Hu Ruoqian, Seydel Karl B, Cohee Lauren M, Zheng Ying, Smith Joseph D
Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA USA.
Department of Bioengineering, University of Washington, Seattle, WA, USA.
J Infect Dis. 2025 Sep 10. doi: 10.1093/infdis/jiaf474.
Sequestration of Plasmodium falciparum-infected erythrocytes (IE) in the microvasculature is a major virulence determinant. While the sequestration of mature stage parasites (trophozoite and schizonts) to vascular endothelium is well established, the conditions that promote ring-stage IE sequestration is less understood. Here, we observed in ring-stage parasites that febrile exposure increased transcript levels of several exported parasite genes involved in the trafficking of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) ligand responsible for adherence to the endothelium of blood vessels. Furthermore, it accelerated PfEMP1 surface display in ring-stage IEs, leading to a twofold increase in their binding in a perfusable 3D human brain microvessel model. Additionally, we observed that parasite exposure enhances the binding of uninfected erythrocytes (UE) in 3D brain microvessels. These findings suggest a complex interplay between fever and parasite biomass in the pathogenesis of cerebral malaria.
恶性疟原虫感染的红细胞（IE）在微血管中的隔离是一个主要的毒力决定因素。虽然成熟阶段寄生虫（滋养体和裂殖体）与血管内皮的隔离已得到充分证实，但促进环状阶段IE隔离的条件尚不太清楚。在这里，我们在环状阶段寄生虫中观察到，发热暴露增加了几个参与负责粘附血管内皮的恶性疟原虫红细胞膜蛋白1（PfEMP1）配体运输的输出寄生虫基因的转录水平。此外，它加速了环状阶段IE中PfEMP1的表面展示，导致其在可灌注的三维人脑微血管模型中的结合增加了两倍。此外，我们观察到寄生虫暴露增强了未感染红细胞（UE）在三维脑微血管中的结合。这些发现表明，在脑型疟疾的发病机制中，发热与寄生虫数量之间存在复杂的相互作用。
