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 show...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.展开更多
基金This work was supported in part by the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant no.XDB29040101)grants from the National Natural Science Foundation of China(Grant nos.31530026 and 31770793)+2 种基金grants from the Beijing Natural Science Foundation of China(Grant no.7192123)the National Science and Technology Major Project(Grant no.2018ZX10101004002004)the Youth Innovation Promotion Association of Chinese Academy of Sciences(Grant No.2018122).
文摘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.
