Malaria and polypeptides of Plasmodium falciparum at the infected erythrocyte surface

Sammanfattning: Malaria is one of the top three most lethal infectious diseases in the world after tuberculosis and HIV. The disease is caused by intracellular parasites of the genus Plasmodium spp. To date, five Plasmodium spp have been linked to human infection, where Plasmodium falciparum is known to cause the most severe forms of the disease, killing upwards of 600 000 people per year. The parasite has a complex life cycle that involves two hosts, the Anopheles mosquito and the human. Humans become infected when bitten by an infected mosquito. In the human host the parasite divides asexually inside the red blood cells, each infected erythrocyte gives rise to 16-32 merozoites that egress and reinvade new red blood cells. A small subset of the parasites also sexually commit and become female or male gametocytes that are crucial for the transmission back to the mosquito. The intra erythrocytic cycle is responsible for causing the symptoms in the human host. During development in the red blood cell the parasite transports and expresses polypeptides on the cell surface making the membrane of the infected erythrocyte “sticky”. These sticky proteins mediate adhesion to uninfected red blood cells forming, so called “rosettes”. Moreover, these proteins can also bind to endothelial cells in the microvasculature, a phenomenon known as “sequestration”, which leads to severe obstruction of the blood flow in the host. Rosetting and sequestration are major pathological features of severe malaria. This thesis focuses on the polypeptides involved in parasite sequestration and rosetting. We identified the RIFIN protein family as a major mediating factor in rosetting and describe how the binding properties are dependent on the ABO blood group antigens of the human host. In addition we utilized single cell RNASeq to study differential gene expression, of important gene families that are linked to sexual commitment, sequestration and rosetting, in malaria-infected red blood cells at single cell resolution. These discoveries regarding the RIFINs are key findings in the development of novel drugs/vaccines against severe malaria disease.