CCR5 deficiency decreases susceptibility to experimental cerebral malaria.
Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic 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. Chemokine receptor-5 (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% to 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 neurologic 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 T-helper 1 (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.
Belnoue
Elodie
E
Département d'Immunologie, Institut Cochin, institut National de la Santé et de la Recherche Médicale (INSERM), Université René Descartes, Hôpital Cochin, Paris, France.
Kayibanda
Michéle
M
Deschemin
Jean-Christophe
JC
Viguier
Mireille
M
Mack
Matthias
M
Kuziel
William A
WA
Rénia
Laurent
L
D000818:Animals; D016026:Bone Marrow Transplantation; D002634:Chemotaxis, Leukocyte; D004198:Disease Susceptibility; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D016779:Malaria, Cerebral / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D010962:Plasmodium berghei; D019713:Receptors, CCR5 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D015996:Survival Rate; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma