The Role of Endoglin in Malaria Pathogenesis

Background: Malaria is one of the main global causes of death from infectious diseases, resulting in 300 500 million clinical cases and more than one million deaths per year. The most severe and complex manifestation of Plasmodium falciparum infection, cerebral malaria (CM), is a neurovascular pathology whose pathogenic mechanisms are far from being completely understood. Critically involved in malaria pathogenesis, either as an anti-inflammatory cytokine/growth factor or as a mediator of apoptosis when released from activated platelets, it the Transforming Growth Factor beta (TGF-ß). The TGF-ß auxiliary receptor endoglin influences vascular tone, modulates TGF-ß response, induces endothelial dysfunction and increases microvascular permeability. We showed recently that during severe malaria Endothelin-1 (ET-1), another potent regulator of the vascular tone with pro- inflammatory properties, was significantly elevated and increases the shedding of endoglin expressing microparticles (MPs). These cellular MPs submicron membrane vesicles generated under conditions of cell activation are potent biological effector with procoagulant and proinflammatory properties contributing significantly to CM pathogenesis. Aims: Based on literature and our own most recent findings, there is a great necessity to analyse in depth the interactions between TGF-ß, endoglin and ET-1 and its impact on the pathogenesis of malaria. In the second part of this project we want to demonstrate the occurrence of cellular MPs in the cerebrospinal fluid (CSF) and we want to investigate the influence of endoglin positive MPs derived from endothelial cells on the expression of TGF-ß, endoglin and adhesion molecules on ependymal cells in culture. Methods: In the proposed research project we want to use different methods such as flow cytometry (FCM), enzyme-linked-immunosorbent-assays (ELISA), Western Blot, quantitative real time polymerase chain reaction (qrtPCR) and endothelial and ependymal cell cultures as well as Plasmodium falciparum parasite cultures. Perspectives: A deeper knowledge and more profound insight into these possible mechanisms of action will elucidate not only pathogenesis of severe especially cerebral malaria but will also contribute to a better understanding of general microvascular pathophysiology and will prove advantageous for a whole spectrum of neurological diseases which involve vascular pathology and inflammatory response, such as subarachnoid haemorrhage or bacterial meningitis. Furthermore, this project will contribute to a better understanding of proand anti-inflammatory mediators, blood flow impairment, endothelial dysfunction and bloodbrain/blood-CSF barrier impairment in malaria.