DRUG DISCOVERY TODAY DISEASE MODELS Cerebral malaria: Which parasite? Which model? Vale ´ry Combes 1 , J. Brian De Souza 2,3 , Laurent Re ´nia 4 , Nicholas H. Hunt 5 , Georges E. Grau 1, * 1 CNRS UMR6020, Immunopathology Group, Faculty of Medicine, IFR48, Universite ´ de la Me ´diterrane ´e, 27 Bd Jean Moulin, F-13385 Marseille Cedex 5, France 2 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, UK WC1E 7HT 3 Department of Immunology and Molecular Pathology, University College London Medical School, Windeyer Building, 46 Cleveland Street, London, UK W1T 4JF 4 De ´partement d’Immunologie, Institut Cochin, INSERM U567, CNRS UMR 8104, Universite ´ Rene ´ Descartes, Paris, France 5 Molecular Immunopathology Unit, Department of Pathology, Medical Foundation Building (K25), University of Sydney, NSW 2006, Australia Cerebral malaria (CM) is a complex condition whose pathogenesis is still poorly understood. Our current knowledge is based on input from clinical, autopsy and genetic studies and from research in model systems, particularly in mice, which are well characterised in terms of histopathology, gene deficiencies and immune response pathways. This short review outlines several in vivo and in vitro models that are highly appropriate for interdisciplinary approaches for the investigation of CM pathogenesis. Section Editors: Bernhard Ryffel – IEM 2815, CNRS, Institut Transgenose, Orleans, France Boris Vargaftig – Institute of Biomedical Sciences, University of Sao Paolo, Sao Paolo, Brazil Introduction Cerebral malaria (CM), a major lethal complication of Plas- modium falciparum infection, is characterised by the seques- tration of parasitised red blood cells (PRBC), particularly in the deep cerebral vascular beds, and by raised levels of proin- flammatory cytokines. Host cells such as leucocytes and platelets are also found in the brain lesions and appear to be implicated in the disease pathogenesis. However, the fine mechanisms leading to cerebral complications remain incompletely understood. Histopathology Analysis of cerebral pathology in human patients is clearly not possible and since postmortem studies merely provide end-point findings, the full extent of events leading to the cerebral syndrome remain largely unresolved. Therefore, understanding the pathogenesis of CM necessarily relies on the use of experimental animal or in vitro models. We will discuss which model and parasite reproduce the features of human CM most accurately (Fig. 1 and Table 1). Primates Malaria infections occur naturally in primates but the out- come of disease in these animals remains largely unknown. However, in the experimental host (rhesus monkey: Macaca mulata), severe disease can be induced with parasites such as P. knowlesi, P. coatneyi and P. fragile [1]. One week after inoculation with P. knowlesi, the majority of monkeys develop acute malaria and die [2]. Postmortem examinations show marked cerebral vascular congestion and plugging of brain capillaries and venules. Infection of rhesus monkeys with P. coatneyi and P. fragile induces the sequestration of PRBC in the brain with the formation of rosettes specific to P. fragile infection, and increased expression of ICAM-1, CD36 and thrombospondin in several organs including brain, as well as the involvement of proinflammatory cytokines such Drug Discovery Today: Disease Models Vol. 2, No. 2 2005 Editors-in-Chief Jan Tornell – AstraZeneca, Sweden Denis Noble – University of Oxford, UK Inflammation and infectious diseases *Corresponding author: G.E. Grau (georges.grau@medecine.univ-mrs.fr) 1740-6757/$ ß 2005 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddmod.2005.05.015 www.drugdiscoverytoday.com 141