Complement and Antibody-Mediated Enhancement of Erythrocyte Invasion by Plasmodium Falciparum

Fiscal Year 2013 Peer Reviewed Medical Research Program Topic Area: Malaria.

Malaria is a blood parasite transmitted by mosquitoes. It is responsible for close to one million deaths per year. Plasmodium falciparum is the deadliest of all the malaria species that infect humans. As part of its life cycle, the parasite invades and destroys red blood cells. Development of a vaccine against P. falciparum has been an elusive goal. One problem with experimental vaccines that are designed with the goal of preventing red blood cell invasion is that while they reduce the growth of the parasite in the test tube, they do not prevent infections when tested in humans. We hypothesize that the explanation for this discrepancy is that some antibodies can actually enhance the ability of the parasite by activating part of the innate immune response known as complement. We know that P. falciparum is able to interact with a complement receptor on the red blood cell surface known as complement receptor 1 (CR1). Activation of the complement cascade likely allows complement proteins to bind to the parasite and this in turn allows it to bind to CR1 facilitating red blood cell invasion. However, the parasite also produces a protein of its own called PfRh4 that is able to interact with CR1. In this proposal, we will carry out preliminary experiments to determine the merit of our hypothesis. We will do this by achieving the following objectives: (1) Test whether anti-malaria antibodies can enhance red cell invasion in the presence of complement. (2) Test the effect of CR1 blockade on the ability of the parasite to enter red blood cells in the absence or presence of complement. (3) Produce a parasite line that lacks PfRh4. (4) Test in a mouse model whether antibodies against malaria can enhance RBC invasion.

Our studies will have important repercussions for the way scientists have gone about testing and developing malaria vaccines that block red blood cell invasion. If we are correct, malaria vaccines will have to be tested to account for the effect of complement. In addition, it is possible that antibodies that do not activate complement may be more effective than those that do activate complement. Therefore, future malaria vaccines may need to be designed to bias the immune response towards the induction of antibodies that do not activate complement.