Malaria is a devastating disease that causes more than one million deaths per year, mainly among children in third world countries. Despite many efforts to control the disease with anti-malarial drugs and insecticides to eliminate mosquito vectors, the appearance of resistant populations of parasites and mosquitoes respectively have impaired the efficacy of these approaches. There is an urgent need for new strategies to control malaria, but there is a lack of detailed knowledge of the basic biological processes of Plasmodium, the causative agent of malaria, that would allow faster development of anti-malaria drugs and vaccines.
We are interested in the first step of malaria infection after the mosquito bite: the infection of the liver. Plasmodium sporozoites that are injected by mosquitoes, reach the circulatory system and migrate to the liver where they infect hepatocytes. Inside hepatocytes, sporozoites replicate forming thousands of merozoites, the next parasitic stage that infects erythrocytes in the blood and causes the pathology associated with malaria. This initial liver stage has tremendous importance for the development of anti-malaria vaccines, as interfering with this initial stage of the disease would stop the infection before causing any clinical symptoms.
We have observed that Plasmodium sporozoites igrate through several hepatocytes before infecting a final one. When the parasite migrates through host cells, literally makes a whole in the membrane of the host cell to invade it. After traversing several cells using this mechanism, finally enters one hepatocyte by invagination of the plasma membrane and formation of a parasitophorous vacuole, within which it would replicate into the merozoite stage. Migration through host cells is necessary to activate Plasmodium sporozoites, inducing exocytosis of proteins that are required for the final infection with formation of a parasitophorous vacuole.We intend to characterize the hepatocyte factor that induces this activation in sporozoites.
Another main interest of our laboratory is the study of the immune response against malaria. More than thirty years ago, it was found that infection of humans with irradiated Plasmodium sporozoites induces protective immunity against malaria. Unfortunately, sporozoites cannot be cultivated in vitro in massive amounts that would be necessary to use them as an anti-malarial vaccine. The mechanism underlying the protection induced by irradiated sporozoites is not well understood. We have discovered that, in contrast with normal sporozoites, hepatocytes infected with irradiated sporozoites undergo apoptosis within 24h of infection. Apoptotic cells are excellent sources of antigens for the immune system that presents the antigens within them to initiate immune responses. We observed that apoptotic hepatocytes infected with irradiated sporozoites are captured by antigen presenting cells, both dendritic cells and macrophages in the liver. We intend to evaluate the importance of this process in the induction of a protective immune response and to apply this knowledge for the development of more effective malaria vaccines.
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