PLASMODIUM GPIS AND · The effect of Plasmodium GPIs on mammalian cells and its role on the course of malaria infections

Final Activity Report Summary - PLASMODIUM GPIS AND (The effect of Plasmodium GPIs on mammalian cells and its role on the course of malaria infections)

Malaria is one of the most important causes of child mortality, killing over 1 million children in Africa alone every year. Plasmodium falciparum is the deadliest species of malaria parasite and is responsible for as many as about half a billion episodes of disease each year, particularly in endemic areas of sub-Saharan Africa and Asia. On entering their host (via the bite of a female Anophele mosquito), Plasmodium sporozoites migrate directly to the liver. Once there, they migrate through several hepatocytes before they infect a final one surrounded by a parasitophorous vacuole where the intrahepatic form of the parasite grows and multiplies before going to the bloodstream where the symptomatic phase of infection begins. Since liver infection is the first obligatory step of a malaria infection, this stage becomes a crucial target for prophylaxis. Although during this period there is an amazing parasite multiplication (each parasite gives rise to 10-30 thousand new parasites in 2-7 days depending on the parasite species) not much is known about its requirements and the strategies developed to survive and to be successful. In fact, we only know that in vitro Plasmodium sporozoites are able to enter any type of cell tested so far but only fully develop inside hepatocytes indicating a crucial role of the host cell in sustaining the growth and development of Plasmodium. This specificity is thought to be mediated by the unique ability of hepatocytes to provide an adequate environment for sporozoite development. However, the reason why Plasmodium sporozoites are only able to develop within hepatocytes remains unknown. With this in mind, we undertook the task of identifying host genes that are important in the modulation of liver infection by the malaria parasite. Kinases are a particularly important class of proteins since they are responsible for nearly all the signalling processes that occur within a cell. The completion of the human genome sequencing project opened the way to the identification of human genes that encode proteins with putative kinase activity. In recent years, the kinome has been regarded as a crucial group of approximately 800 genes, implicated in a growing number of cellular processes. For these reasons, we decided to tackle the ambitious task of screening the human kinome for its role in facilitating or preventing infection of liver cells by Plasmodium parasites. In order to achieve the goals outlined above, each component of the kinome must be evaluated individually for its importance in infection. RNA interference is a novel technique whereby expression of individual genes can be knocked-down in vitro, followed by the monitoring of the effects of this (partial) silencing. Thus, we made use of this technique to systematically knock-down each of the kinase-encoding genes in a human hepatoma cell line and determine in vitro the resulting effect on infection by Plasmodium parasites. The results obtained by us until now led to the identification of several host genes with putative kinase activity that appear to have a strong influence in infection of human hepatocytes by P. berghei sporozoites. This paves the way of understanding how Plasmodium interacts with its host cell and allowing to design rational ways of preventing this devastating disease.

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