Identification of fikk gene expression specific to severe malarial syndromes in Malian children

Abstract

Plasmodium falciparum is the most common and virulent malaria parasite. As the primary species responsible for severe malaria, it continues to be a leading cause of mortality in the developing world. Children under the age of five are overwhelmingly affected, accounting for most deaths from malaria. P. falciparum is unique among Plasmodium species for having multiple members of the fikk multigene family, which encodes serine/threonine kinases. During intra-erythrocytic infection, P. falciparum actively exports 18-26 FIKKs into the infected erythrocyte. These kinases are predicted to facilitate the activation and trafficking of membrane proteins within infected erythrocytes, contributing to the remodeling of the erythrocytic membrane and its highly variable surface antigens. Given the association of parasite erythrocyte surface antigens and severe malarial disease, we hypothesized that severe malaria cases feature elevated expression of a subset of fikks compared to matched uncomplicated malaria controls. We investigated the differential expression of fikk kinases in severe clinical syndromes of P. falciparum malaria in a matched case-control study in Mali. Using a custom pipeline, we compared fikk expression in cases of cerebral malaria (CM), severe malaria anemia (SMA), and a combined syndrome featuring both CM and SMA (CM+SMA) to matched uncomplicated malaria controls (UM). Preliminary findings with 64 total subjects indicate the differential expression of several fikks in severe disease compared to matched controls. One fikk gene had significantly increased expression in CM cases compared to matched uncomplicated malaria controls (N=14 pairs, P<0.02; Wilcoxon signed-rank test). We identified a characteristic fikk expression profile specific to the combined CM+SMA syndrome involving four FIKKs. We are examining host immune responses to FIKK proteins using a custom protein microarray. We are assessing the suitability of a subset of FIKKs as targets for vaccine and therapeutic development for severe malaria, particularly if they are natural targets of the host immune system.