Final Report Summary - LIPID & INFECTION (The function and dynamic of cholesterol during Plasmodium liver stage infection) Plasmodium parasites are the causative agents of malaria, amongst the most prevalent and severe human infectious diseases. Liver infection by Plasmodium sporozoites is the first obligatory step of malaria and a quite attractive target for prophylactic strategies against the disease. At this stage, each sporozoite invades a single hepatocyte and develops into thousands of merozoites that are released into the bloodstream. Preliminary results of the host laboratory have clearly shown that a hepatocyte receptor, SR-BI, plays a crucial role both in invasion and development of Plasmodium in the liver. In its physiological role, SR-BI is a central component of the cholesterol uptake by cells. Thus, the overall aim of this project was to reveal whether and how cholesterol uptake is critical for hepatocyte infection by Plasmodium. By using various cell biology approaches, we thus showed that: 1) uptake of exogenous cholesterol, rather than host cell de novo biosynthesis, is important for development of Plasmodium liver stage. 2) live imaging of fluorescent cholesterol and photobleaching experiments demonstrated that cholesterol is uptaken from lipoproteins and that cholesteryl ester rather than free cholesterol is transported very efficiently inside the developing parasite. 3) siRNA screen revealed that following cholesterol uptake through SR-BI, SCP2 may play a role in the transport and that FASN and SOATs in esterifying cholesterol prior to its uptake by exo-erythrocytic form of Plasmodium. Achieving this work has highlighted a new host pathway scavenged by Plasmodium in the liver to accomplish its own development and further establish a symptomatic blood infection. This will hopefully provide in the near future a rationale for a potential cholesterol-based anti-malarial prophylactic intervention, and contribute to the European excellence by reaching one of the main goals of the Seventh Framework Programme regarding action to confront infectious diseases.
