Identification of Plasmodium falciparum-specific protein PIESP2 as a novel virulence factor related to cerebral malaria.

Cerebral malaria (CM) is the most severe complication caused by Plasmodium falciparum infection. The pathophysiological changes caused by parasite virulence factors and the human immune response to parasites contribute to CM. To date, very few parasite virulence proteins have been found to participate in CM. Here, we employed comparative genomics analysis and identified parasite-infected erythrocyte specific protein 2 (PIESP2) to be a CM-related protein. We conducted further experimental investigations and found that PIESP2 is an immunogenic protein. PIESP2 expression begins at the early trophozoite stage and progressively increases with parasite development. Although PIESP2 proteins mainly reside within infected red blood cells (IRBCs), some of them are present on the IRBC surface at the pigmented stage. Moreover, blockage of PIESP2 by antiserum apparently inhibited the adhesion of IRBCs to brain microvascular endothelial cells (BMECs). Western blot analysis detected the binding of PIESP2 to BMECs. Transcriptional analysis revealed that the binding of PIESP2 to BMECs can increase the expression of genes involved in the inflammatory response but decrease the expression of genes related to the anchoring junction. Overall, PIESP2 might be associated with CM by mediating the sequestration of IRBCs, inducing the inflammation response, and impairing the integrity of blood-brain barrier.