Abstract
Malaria is a devastating disease caused by Plasmodium parasites that are transmitted by Anopheles mosquitoes. Novel drugs and vaccines are urgently needed since drug-resistant strains are spreading rapidly and the only vaccine available has limited efficacy. During various stages of its life-cycle, the parasite is under attack from the human complement system. The complement system is part of the innate immune system and consists of soluble serum proteins that, upon activation, initiate lysis, phagocytosis and inflammation. In the human host, Plasmodium sporozoite and merozoite stages move freely in the circulation thereby being exposed to complement proteins. Likewise, Plasmodium gamete stages that emerge from infected red blood cells after ingestion by mosquitoes are exposed to human complement. The effect of complement on parasite survival and whether the parasite actively evades complement is poorly understood. Newly developed methodologies allow, for the first time, to examine the roles of complement and complement evasion in detail. I hypothesize that activated human complement is detrimental for sporozoite, merozoite and gamete survival and that these life-cycle stages have developed an array of mechanisms to prevent activation of complement pathways. I further hypothesize that complement evasion mechanisms are excellent targets for potent immune therapeutics. I aim to obtain a comprehensive insight in complement evasion strategies of Plasmodium parasites in relation to complement-mediated parasite clearance. In this project, I will systematically identify and characterize Plasmodium proteins that inhibit human complement and using knockout strains study the impact of complement on parasite survival. Furthermore, I will isolate functional human antibodies against these complement inhibitors which will guide future vaccine development. Finally, I will develop biomolecules that interfere with complement evasion strategies and engineered antibodies with enhanced complement-dependent cytotoxicity against all parasite stages. Altogether this study will provide unprecedented insight in complement-malaria parasite interactions and leads for future intervention development.
Netherlands