Survival strategies of Plasmodium berghei exoerythrocytic forms (EEF) in hepatocytes

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Survival of intracellular parasites depends on their ability to circumvent apoptosis of the host cell. Using the rodent parasite Plasmodium berghei as a model system we investigate survival strategies of Plasmodium parasites in hepatocytes from entry of sporozoites to the release of merozoites. In course of our ongoing studies we could show that during the first two days of infection the parasite protects the host cell from apoptosis, where as it induces apoptosis on the third day upon formation of merozoites. It is planned to study parasite dependent regulation of pro- and anti-apoptotic host signalling pathways as well as the molecular events leading to the dramatic changes in the host cell during merogony. Another goal of this proposal is the characterisation of merozoite formation in hepatocytes. This part of the project is based on our observation that parasitised hepatic cells round off and float in the supernatant briefly before they undergo apoptosis. Floating infected cells can easily be separated from non-infected adherent cells offering for the first time the possibility to study liver-derived Plasmodium parasites in detail. The identification and specific inhibition of parasite proteins needed for merozoite survival is envisaged. Apart from a more gereal approach to identify those parasite proteins we will focus on parasite proteases which are involved in the destruction of host cell membranes during the release of merozoites from hepatocytes.