Cerebral malaria (CM) is a life-threatening diffuse encephalopathy caused by Plasmodium falciparum, in which the destruction of the blood–brain barrier (BBB) is the main cause of death. However, increasing evidence has shown that antimalarial drugs, the current treatment for CM, do little to protect against CM-induced BBB damage. Therefore, a means to alleviate BBB dysfunction would be a promising adjuvant therapy for CM. The adhesion molecule CD146 has been reported to be expressed in both endothelial cells and proinflammatory immune cells and mediates neuroinflammation. Here, we demonstrate that CD146 expressed on BBB endothelial cells but not immune cells is a novel therapeutic target in a mouse model of experimental cerebral malaria (eCM). Endothelial CD146 is upregulated during eCM development and facilitates the sequestration of infected red blood cells (RBCs) and/or proinflammatory lymphocytes in CNS blood vessels, thereby promoting the disruption of BBB integrity. Mechanistic studies showed that the interaction of CD146 and Galectin-9 contributes to the aggregation of infected RBCs and lymphocytes. Deletion of endothelial CD146 or treatment with the anti-CD146 antibody AA98 prevents severe signs of eCM, such as limb paralysis, brain vascular leakage, and death. In addition, AA98 combined with the antiparasitic drug artemether improved the cognition and memory of mice with eCM. Taken together, our findings suggest that endothelial CD146 is a novel and promising target in combination with antiparasitic drugs for future CM therapies.

脑型疟疾 (CM) 是由恶性疟原虫引起的危及生命的弥漫性脑病，其中血脑屏障（BBB）的破坏是死亡的主要原因。然而，越来越多的证据表明，目前治疗 CM 的抗疟疾药物几乎不能防止 CM 引起的 BBB 损伤。因此，缓解 BBB 功能障碍的方法将是 CM 的一种有希望的辅助治疗。据报道，粘附分子 CD146 在内皮细胞和促炎免疫细胞中均表达并介导神经炎症。在这里，我们证明了在 BBB 内皮细胞而非免疫细胞上表达的 CD146 是实验性脑疟疾 (eCM) 小鼠模型中的新治疗靶点。内皮细胞 CD146 在 eCM 发育过程中被上调，并有助于隔离受感染的红细胞 (RBC) 和/或 CNS 血管中的促炎淋巴细胞，从而促进 BBB 完整性的破坏。机制研究表明，CD146 和 Galectin-9 的相互作用有助于受感染的红细胞和淋巴细胞的聚集。删除内皮 CD146 或用抗 CD146 抗体 AA98 治疗可防止 eCM 的严重迹象，如肢体麻痹、脑血管渗漏和死亡。此外，AA98与抗寄生虫药蒿甲醚联合使用可改善eCM小鼠的认知和记忆。总之，我们的研究结果表明，内皮 CD146 与抗寄生虫药物联合用于未来的 CM 治疗是一种新的且有希望的靶点。删除内皮 CD146 或用抗 CD146 抗体 AA98 治疗可防止 eCM 的严重迹象，如肢体麻痹、脑血管渗漏和死亡。此外，AA98与抗寄生虫药蒿甲醚联合使用可改善eCM小鼠的认知和记忆。总之，我们的研究结果表明，内皮 CD146 与抗寄生虫药物联合用于未来的 CM 治疗是一种新的且有希望的靶点。删除内皮 CD146 或用抗 CD146 抗体 AA98 治疗可防止 eCM 的严重迹象，如肢体麻痹、脑血管渗漏和死亡。此外，AA98与抗寄生虫药蒿甲醚联合使用可改善eCM小鼠的认知和记忆。总之，我们的研究结果表明，内皮 CD146 与抗寄生虫药物联合用于未来的 CM 治疗是一种新的且有希望的靶点。