Objectif
Plasmodium parasites are the causative agents of malaria, amongst the most prevalent and severe human infectious diseases. Plasmodium sporozoites are injected into the mammalian host during the bite of an anopheline mosquito, and rapidly migrate to the liver where they invade hepatocytes. Once inside a hepatocyte, a single sporozoite initiates a developmental program whereby it gives rise to thousands of merozoites, which are released into the blood stream a few days later, initiating the clinical phase of malaria infection. Sporozoites are capable of entering any cell type tested thus far in vitro, and can even initiate transformation into exo-erythrocytic forms extracellularly, but can only undergo schizogony and generate infectious merozoites in a particular environment, which appears to be provided exclusively by hepatocytes and hepatoma cell lines. This strongly suggests a crucial role of the host cell in providing a distinct niche that supports Plasmodium growth and development. One distinctive feature of hepatocytes when compared to other epithelial cells is their mode of polarization. The general importance of host cell polarity for a liver stage Plasmodium infection has not been investigated. I propose to analyze the role of one unique aspect of hepatocyte biology, the hepatic mode of polarization, in creating the hepatocyte niche that uniquely supports liver stage Plasmodium growth and development. I will address this question by taking a broad approach to characterize the stages of Plasmodium development in WIF-B cells, which display hepatic polarity and to characterize the polarization state of Huh-7 cells, a hepatoma line widely used to assess infection. In a complementary candidate molecule approach, I will characterize the requirement for the host EMK1 kinase, which has a known role in generating hepatic polarity, and the siRNA mediated knockdown of which has a reproducible effect on Plasmodium infection.
Champ scientifique
Mots‑clés
Thème(s)
Appel à propositions
FP7-PEOPLE-2007-2-1-IEF
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Régime de financement
MC-IEF - Intra-European Fellowships (IEF)Coordinateur
1649 028 Lisboa
Portugal