Approximately 300 million clinical episodes and ~ 450,000 deaths are caused by malaria annually, making it one of the deadliest tropical parasitic diseases. Humans can be infected by 6 Plasmodium species, however 95% of all fatalities are caused by a single species, Plasmodium falciparum. The severity of P. falciparum malaria is associated with the method by which the parasite avoids filtration by the spleen. It does so by two means: 1) cytoadhesion of the infected red blood cell (iRBC) to the vascular endothelium and 2) rigidification of the host cell leading to retention of iRBCs in the microvasculature. In both cases, the accumulation of infected erythrocytes results in obstruction of blood flow and a strong local inflammatory response which can cause severe cerebral malaria leading to stroke and death. Cytoadhesion is predominantly mediated by a parasite protein called PfEMP1 that is transported onto the surface of the infected red blood cell. PfEMP1 binds to receptors on endothelial cells in various organs, sequestering the infected cell away from the peripheral circulation. Interestingly, a rapid increase of PfEMP1 surface translocation, cytoadhesion and RBC rigidity on relatively short timeframes (1-2 hours) has been observed upon fever. This implies that in addition to the well-studied differential PfEMP1 variant expression, a yet unknown mechanism must exist that allows the parasite to sense fever in the host and rapidly control its pathogenesis traits in response.
We have recently identified members of a parasite kinase family that are exported into the RBC and phosphorylate human and parasite exported proteins important for controlling cytoadhesion and rigidification. This kinase family, the FIKK kinases, contains ~20 members which are exported into the host cell only by P. falciparum and a sub-genus of 6 related Plasmodium species that infect great apes, the Laverania. None of the other human-infecting Plasmodium species contains any predicted exported kinase, implying their presence may contribute to the particular virulence of P. falciparum. The FIKK kinase family evolved from a single, non-exported ancestor ~ 1 million years ago, and 17 of the 19 FIKKs found in P. falciparum appear to have been conserved across the sub-genus since then. A key conserved component within the Laverania, that distinguishes it from other Plasmodium species, is the presence of PfEMP1, suggesting that at least some FIKKs and PfEMP1 may have co-evolved.
We found several FIKK kinases that do not play an apparent role in RBC remodelling under standard culturing conditions, despite being expressed. This led us to consider that certain FIKKs may be activated during certain environmental conditions present in the host. One of these conditions is fever, a hallmark of severe human malaria which leads to increased PfEMP1 surface presentation and cytoadhesion within hours. Another common environmental condition in the host is the sickle cell trait, known as the HbAS genotype or the related HbAC variant. PfEMP1 surface translocation and cytoadhesion is markedly reduced in RBCs from patients with sickle cell trait, likely as a result of elevated reactive oxygen species (ROS) in these cells that lead to direct oxidation of proteins. ROS also accumulates in RBCs under hypoxic conditions. This is found in areas of high parasite sequestration in the microvasculature, which could therefore lead to a local effect of ROS on parasite infected RBCs. Treatment of iRBCs with diamide, an oxidising agent indeed mimics the ROS effect observed in HbAS cells.
