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Prepublished online as a Blood First Edition Paper on January 30, 2003; DOI 10.1182/blood-2002-05-1493.
Submitted May 21, 2002
Accepted January 14, 2003
CCR5 deficiency decreases susceptibility to experimental cerebral malaria
Elodie Belnoue, Michele Kayibanda, Jean-Christophe Deschemin, Mireille Viguier, Matthias Mack, William A Kuziel, and Laurent Renia*
Departement d'Immunologie, Institut Cochin, Paris, France
Medical Policlinic, University of Munich, Munich, Germany
Department of Microbiology and Institute of Cellular and Molecular Biology, University of Texas, Austin, TX, USA
* Corresponding author; email: renia{at}cochin.inserm.fr.
Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathological features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T cell subset of these brain-sequestered leukocytes is critical for progression to CM. The chemokine receptor CCR5 is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70-85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurological signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in Th1 cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM) chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.
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