Microvesiculation and cell interactions at the brain–endothelial interface in cerebral malaria pathogenesis Vale ´ ry Combes a , Fatima El-Assaad a , Dorothe ´ e Faille a , Ronan Jambou a,c , Nicholas H. Hunt b , Georges E.R. Grau a, * a Department of Pathology, Vascular Immunology Unit, Australia b Molecular Immunopathology Unit, Department of Pathology, Sydney Medical School & Bosch Institute, The University of Sydney, Sydney, Australia c De ´partement de Parasitologie & Mycologie, Institut Pasteur, Paris, France Contents 1. Cerebral malaria, still a major world health problem .................................................................... 140 2. Pathogenic mechanisms: neurovascular aspects of CM ................................................................... 141 2.1. Some particularities of anti-malarial immunity ................................................................... 141 2.2. Central role of endothelial activation/alteration ................................................................... 142 2.2.1. Evidence of endothelial damage in CM .................................................................. 142 2.2.2. ‘‘Mediator-induced’’ endothelial alteration: cytokines and receptors ........................................... 143 2.2.3. ‘‘Host cell induced’’-endothelial alteration: ‘‘inside and outside the vessel’’ ..................................... 143 2.3. Microparticles (MP) in CM .................................................................................... 146 2.3.1. General features of MP ............................................................................... 146 2.3.2. MP changes in CM: patients, mice ...................................................................... 146 2.3.3. Effect of MP blockade in vivo and in vitro ................................................................ 146 2.3.4. Consequences of MP overproduction: effects on target cells and in vivo distribution .............................. 147 3. Conclusions and perspectives ....................................................................................... 148 Acknowledgements ............................................................................................... 148 References ...................................................................................................... 148 1. Cerebral malaria, still a major world health problem Malaria remains a major problem of public health, since WHO estimates indicate that each year in excess of 300 million people are infected by Plasmodium falciparum worldwide (Snow et al., 2005). More than two million African children die each year of severe malaria, mainly cerebral malaria (CM) and severe malarial anaemia. Currently there are 109 malaria-endemic countries with more than three billion individuals at risk Progress in Neurobiology 91 (2010) 140–151 ARTICLE INFO Article history: Received 16 February 2009 Received in revised form 2 April 2009 Accepted 5 January 2010 Keywords: Cerebral malaria Cell–cell interactions Microparticles Endothelium ABSTRACT Cerebral malaria (CM) is still a major world health problem whose pathogenic mechanisms remain incompletely understood. After reviewing some particularities of anti-malarial immunity, we focus here on the neurovascular aspects of CM. We specifically address the central role of endothelial activation and alteration in disease pathogenesis. We discuss the respective roles of ‘‘mediator-induced’’ versus ‘‘host cell-induced’’ mechanisms of endothelial alteration. The former include cytokines, chemokines and their receptors, while the latter encompass cells located inside and outside the vessel, notably glial cells. We also present evidence for a pathogenic role for membrane microparticles (MP) in CM, based on studies in African patients and in a recognised mouse model. Intervention studies on MP production, via either gene knockout or pharmacological inhibition, can prevent the neurological syndrome and its associated mortality, suggesting potential new therapeutic avenues. ß 2010 Elsevier Ltd. All rights reserved. Abbreviations: ABCA1, ATP-binding cassette transporter A1; CM, cerebral malaria; CM-R, CM-resistant; CM-S, CM-susceptible; EC, endothelial cells; HBEC, human brain endothelial cells; MP, microparticles; MRI, multimodal resonance imaging; PfEMP-1, P. falciparum erythrocyte membrane protein-1; PRBC, parasitised red blood cells; PS, phosphatidylserine; PbA, Plasmodium berghei ANKA; P. falciparum, Plasmodium falciparum. * Corresponding author at: Vascular Immunology Unit, Department of Pathology, Sydney Medical School, The University of Sydney, Medical Foundation Building (K25), 92-94 Parramatta Rd, Camperdown, NSW 2042, Australia. Tel.: +61 2 9036 3260; fax: +61 2 9036 3177. E-mail address: georges.grau@sydney.edu.au (Georges E.R. Grau). Contents lists available at ScienceDirect Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio 0301-0082/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2010.01.007