Plasmodium Falciparum Surface Antigens Thrombospondin-Related Anonymous Protein (TRAP) And Circumsporozoite Protein (CS) Inhibit Complement Mediated Killing

Malaria remains the world's most devastating tropical infectious disease, with as many as 40% of the world population living in perilous areas. It is caused by a parasite called Plasmodium, which is transmitted by the bites of infected mosquitoes. In the human body, the parasites multiply in the liver, and then infect the red blood cells. Sporozoites (the stage that infects liver cells) express circumsporozoite (CS) protein and the thrombospondin related anonymous protein (TRAP), which are implicated in recognition of, and entry into, hepatocytes. These proteins contain highly conserved thrombospondin domain motives (TSP domains), structural motifs also found in thrombospondin-1 and properdin. Previous data show that thrombospondin acts as an effective competitive inhibitor of properdin-dependent complement activation, binding firmly to the same target complex as properdin. My hypothesis is that the TSP domains containing Plasmodium TRAP and CS proteins have a similar activity, inhibiting host complement activation and thus protecting the parasite from complement attack. Recombinant TRAP and CS proteins, and fragments thereof, were produced in prokaryotic expression systems and tested in vitro for complement inhibitory activity. The proteins decreased deposition of C3, the central component of complement, via the lectin and alternative pathways. Moreover, adding proteins to serum reduces the lysis of guinea pig RBCs, indicating that the terminal pathway and MAC formation are inhibited. Mouse monoclonal antibody was produced from a C-terminal fragment of CS protein. This mAb could block the inhibition of complement activity by CS protein. This could open up the possibility of new therapies and vaccine targets that exploit this mechanism to interfere with the parasite life cycle at this stage.