The Plasmodium falciparum -Specific Protein PIESP2 Can Mediate the Sequestration of Infected Erythrocytes to Brain Microvascular Endothelial Cells (BMECs) and Induce Inflammatory Response in BMECs

Background: Cerebral malaria (CM) is the most severe complication caused by Plasmodium falciparum infection. The pathophysiological changes caused by parasite virulent factors and human immune response to parasites contribute to CM. To date, very few parasite virulent proteins have been found to participate in CM. Identifying new parasite proteins involved in CM may provide new directions for possible intervention. Methods: Comparative genomic analysis was performed and parasite-infected erythrocyte specific protein 2 (PIESP2) was identified to be a CM-related candidate protein. The immunogenic property of PIESP2 was investigated. Its expression and localization in infected red blood cells (IRBCs) during intraerythrocytic stage were characterized. Adhesion assay and RNA-seq were adopted to evaluate the role of PIESP2 in the development of CM. Findings: PIESP2 is an immunogenic protein. Its expression begins at the early trophozoite stage and progressively increases with parasite development. PIESP2 mainly resides inside IRBCs but few of them are present on IRBC surface at the late trophozoite stage. Blockage of PIESP2 by antiserum apparently inhibited the adhesion of IRBCs to brain microvascular endothelial cells (BMECs). Moreover, PIESP2 could directly bind to BMECs, subsequently leading to an increase in the expression of genes involved in inflammatory response in BMECs and a decrease in the expression of genes related to anchoring junction. Interpretation: The P. falciparum specific protein PIESP2 may contribute to CM by mediating the sequestration of IRBCs to BMECs, inducing inflammatory response and impairing the integrity of the blood–brain barrier. Funding Statement: This work was supported by a grant from the National Natural Science Foundation of China (Grant No. 31600615). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: Ethical approval was given by the First Affiliated Hospital Ethics Committee of Fourth Military Medical University with reference number KY20163289-1. All experimental procedures were performed in accordance with relevant institutional and national guidelines and approved by the Institutional Animal Care and Use Committee of Fourth Military Medical University.