Interferon-gamma is essential for the development of cerebral malaria.
Infection with Plasmodium berghei ANKA (PbA) causes fatal cerebral malaria (CM). While a pathogenic role for tumor necrosis factor (TNF) has been established, we asked whether a disruption of interferon-gamma (IFN-gamma) signaling would modulate CM. We demonstrate here that IFN-gammaR-deficient mice are completely protected from CM. PbA-induced release of TNF and up-regulation of endothelial intercellular adhesion molecule (ICAM)-1 expression, recruitment of mononuclear cells, and cerebral microvascular damage with vascular leakage occur only in wild-type mice. Protected mice die at a later time of severe anemia and overwhelming parasitemia. Resistance to CM in IFN-gammaR-deficient mice is associated with reduced serum TNF levels, reduced interleukin-12 expression in the brain and increased T-helper 2 cytokines. In conclusion, IFN-gamma is apparently required for PbA-induced endothelial ICAM-1 up-regulation and subsequent microvascular pathology, resulting in fatal CM. In the absence of IFN-gamma signaling, ICAM-1 and TNF up-regulation is reduced; hence, PbA infection fails to cause fatal CM.
Rudin
W
W
Swiss Tropical Institute, University of Basel, Switzerland.
Favre
N
N
Bordmann
G
G
Ryffel
B
B
D000740:Anemia / Q000209:etiology / Q000276:immunology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000502:physiology*; D007964:Leukocytosis / Q000209:etiology / Q000276:immunology; D016779:Malaria, Cerebral / Q000209:etiology* / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018512:Parasitemia / Q000209:etiology / Q000276:immunology; D010962:Plasmodium berghei / Q000276:immunology; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000096743:Interferon gamma Receptor
D016207:Cytokines; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor