Analysis of platelets during malaria infection, and their interaction with Plasmodium-infected erythrocytes

Abstract

Malaria is an infectious disease caused by Plasmodium parasites, transmitted by the female Anopheles mosquito. Malaria can cause mild symptoms as well as more severe complications which may lead to death. Annually, there are half a million deaths worldwide with millions more newly infected with malaria. Although antimalarials exist, due to the prevalence of drug resistance, novel, more effective treatments are needed to combat malaria by aiding the host immune response. One of the earliest signs of a malarial infection is a decrease in the concentration of platelets in the blood of infected individuals -clinically referred to as thrombocytopenia. Platelets have been shown to play a protective role during a malaria infection by targeting the parasite vacuole via platelet factor 4 (PF4). PF4 is only released from activated platelets upon contact with infected red blood cells (iRBCs), and not uninfected red blood cells (uRBCs). The molecules responsible for platelet activation and subsequent release of PF4 from iRBCs were to be determined in this thesis. Platelet activation via infected lysate from trophozoite stage parasites was originally observed but not consistent. Purified trophozoites were unable to activate platelets hence the molecule of interest was unable to be determined. The second part of this thesis was to measure the contribution of platelets binding to RBCs in thrombocytopenia. It has been previously shown that platelets bind preferentially to iRBCs compared with uRBCs. No definite mechanism of thrombocytopenia has been elucidated to date, although a number, such as splenic pooling and endothelial activation, have been thought to play a role. In this thesis, it was hypothesised that platelet binding and subsequent clearance may be responsible for malaria-induced thrombocytopenia. Before the onset of thrombocytopenia, preferential binding of platelets to iRBCs was observed and although platelets were cleared more quickly in infected mice, the contribution of platelet bound RBCs was unable to be definitely identified. Show more