Pathogen Genomics Laboratory, Bioscience Program, Biological and Environmental Sciences and Engineering (BESE) Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Microbiol Spectr. 2024 Jul 2;12(7):e0072724. doi: 10.1128/spectrum.00727-24. Epub 2024 Jun 12.
A hallmark of cerebral malaria (CM) is sequestration of -infected erythrocytes (IE) within the brain microvasculature. Binding of IE to endothelium reduces microvascular flow and, combined with an inflammatory response, perturbs endothelial barrier function, resulting in breakdown of the blood-brain barrier (BBB). Cytoadherence leads to activation of the endothelium and alters a range of cell processes affecting signaling pathways, receptor expression, coagulation, and disruption of BBB integrity. Here, we investigated whether CM-derived parasites elicit differential effects on human brain microvascular endothelial cells (HBMECs), as compared to uncomplicated malaria (UM)-derived parasites. Patient-derived IE from UM and CM clinical cases, as well as non-binding skeleton-binding protein 1 knockout parasites, were overlaid onto tumour necrosis factor (TNF)-activated HBMECs. Gene expression analysis of endothelial responses was performed using probe-based assays of a panel of genes involved in inflammation, apoptosis, endothelial barrier function, and prostacyclin synthesis pathway. We observed a significant effect on endothelial transcriptional responses in the presence of IE, yet there was no significant correlation between HBMEC responses and type of clinical syndrome (UM or CM). Furthermore, there was no correlation between HBMEC gene expression and both binding itself and level of IE binding to HBMECs, as we detected the same change in endothelial responses when employing both binding and non-binding parasites. Our results suggest that interaction of IE with endothelial cells in this co-culture model induces some endothelial responses that are independent of clinical origin and independent of the expression of the major variant antigen erythrocyte membrane protein 1 on the IE surface.
Cerebral malaria (CM) is the most prevalent and deadly complication of severe infection. A hallmark of this disease is sequestration of -infected erythrocytes (IE) in brain microvasculature that ultimately results in breakdown of the blood-brain barrier. Here, we compared the effect of parasites derived from uncomplicated malaria (UM) and CM cases on the relative gene expression of human brain microvascular endothelial cells (HBMECs) for a panel of genes. We observed a significant effect on the endothelial transcriptional response in the presence of IE, yet there is no significant correlation between HBMEC responses and the type of clinical syndrome (UM or CM). Furthermore, there was no correlation between HBMEC gene expression and both binding itself and the level of IE binding to HBMECs. Our results suggest that interaction of IE with endothelial cells induces endothelial responses that are independent of clinical origin and not entirely driven by surface erythrocyte membrane protein 1 expression.
脑型疟疾（CM）的一个标志是受感染的红细胞（IE）在脑微血管内的隔离。IE 与内皮细胞的结合会降低微血管的流动，再加上炎症反应，会扰乱内皮屏障功能，从而导致血脑屏障（BBB）的破坏。细胞粘附会导致内皮细胞的激活，并改变一系列影响信号通路、受体表达、凝血和 BBB 完整性的细胞过程。在这里，我们研究了 CM 来源的寄生虫与简单疟疾（UM）来源的寄生虫相比，是否会对人脑微血管内皮细胞（HBMEC）产生不同的影响。从 UM 和 CM 临床病例中分离出的患者源性 IE，以及非结合骨架结合蛋白 1 缺失的寄生虫，被覆盖在肿瘤坏死因子（TNF）激活的 HBMEC 上。使用涉及炎症、细胞凋亡、内皮屏障功能和前列环素合成途径的一组基因的探针检测试剂盒，对内皮反应的基因表达进行了分析。我们观察到 IE 存在时内皮转录反应有显著影响，但 HBMEC 反应与临床综合征类型（UM 或 CM）之间没有显著相关性。此外，HBMEC 基因表达与结合本身和 IE 与 HBMEC 结合的水平之间没有相关性，因为我们在使用结合和非结合寄生虫时都检测到内皮反应的相同变化。我们的研究结果表明，IE 与共培养模型中的内皮细胞相互作用诱导了一些内皮反应，这些反应与临床来源无关，也与 IE 表面主要变体抗原 1 红细胞膜蛋白的表达无关。
脑型疟疾（CM）是严重疟疾感染最常见和最致命的并发症。这种疾病的一个标志是 IE 在脑微血管中的隔离，最终导致血脑屏障的破坏。在这里，我们比较了来自简单疟疾（UM）和 CM 病例的寄生虫对人脑血管内皮细胞（HBMEC）的一组基因相对基因表达的影响。我们观察到 IE 存在时内皮转录反应有显著影响，但 HBMEC 反应与临床综合征类型（UM 或 CM）之间没有显著相关性。此外，HBMEC 基因表达与结合本身和 IE 与 HBMEC 结合的水平之间没有相关性。我们的研究结果表明，IE 与内皮细胞的相互作用诱导了一些内皮反应，这些反应与临床来源无关，也不完全由 IE 表面的 1 红细胞膜蛋白的表达驱动。
