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Infection and Immunity, November 2005, p. 7736-7746, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7736-7746.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Whole-Body Imaging of Sequestration of Plasmodium falciparum in the Rat

Microbiology & Tumorbiology Centre (MTC), Karolinska Institutet, and Swedish Institute for Infectious Disease Control (SMI), Box 280, SE-171 77 Stockholm,¹ Department of Nuclear Medicine, Karolinska University Hospital (KUS), Solna,² Department of Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden³

Received 16 March 2005/ Returned for modification 20 April 2005/ Accepted 25 July 2005

The occlusion of vessels by packed Plasmodium falciparum-infected (iRBC) and uninfected erythrocytes is a characteristic postmortem finding in the microvasculature of patients with severe malaria. Here we have employed immunocompetent Sprague-Dawley rats to establish sequestration in vivo. Human iRBC cultivated in vitro and purified in a single step over a magnet were labeled with ^99mtechnetium, injected into the tail vein of the rat, and monitored dynamically for adhesion in the microvasculature using whole-body imaging or imaging of the lungs subsequent to surgical removal. iRBC of different lines and clones sequester avidly in vivo while uninfected erythrocytes did not. Histological examination revealed that a multiadhesive parasite adhered in the larger microvasculature, inducing extensive intravascular changes while CD36- and chondroitin sulfate A-specific parasites predominantly sequester in capillaries, inducing no or minor pathology. Removal of the adhesive ligand Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), preincubation of the iRBC with sera to PfEMP1 or preincubation with soluble PfEMP1-receptors prior to injection significantly reduced the sequestration. The specificity of iRBC binding to the heterologous murine receptors was confirmed in vitro, using primary rat lung endothelial cells and rat lung cryosections. In offering flow dynamics, nonmanipulated endothelial cells, and an intact immune system, we believe this syngeneic animal model to be an important complement to existing in vitro systems for the screening of vaccines and adjunct therapies aiming at the prevention and treatment of severe malaria.

Editor: J. F. Urban, Jr.

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