Involvement of IFN-gamma receptor-medicated signaling in pathology and anti-malarial immunity induced by Plasmodium berghei infection.
IFN-gamma has been implicated in the pathogenesis of experimental cerebral malaria (ECM). We have used mice lacking the alpha chain of the IFN-gamma receptor (KO mice) to define its role in the pathogenesis of ECM. Infected KO mice did not develop ECM and showed no leukocyte or parasite sequestration in the brain, and no hemorrhages. The resistance of KO mice to ECM was associated with the absence of any increases of TNF-alpha and ICAM-1 proteins in the brain, which are both essential for ECM. Wild-type (WT) mice which do not develop ECM, despite increased local production of TNF-alpha protein, showed no leukocyte accumulation in the brain and this was correlated with the absence of ICAM-1 protein from brain microvessels. KO mice infected with 106 parasitized erythrocytes (PE) of Plasmodium berghei ANKA (PbA) did not develop ECM, but they had high parasitemia and died earlier than WT mice which did not develop ECM. However, KO mice did not develop higher parasitemia than WT mice when both groups were infected with a lower dose (5x10(5) PE) of PbA-infected red blood cells. This indicates that different doses of PE may trigger different IFN-gamma responses and that there may be a threshold concentration for protection against parasitemia.
Amani
V
V
INSERM U511, CHU Pitié-Salpêtrière, Université Paris, France.
Vigário
A M
AM
Belnoue
E
E
Marussig
M
M
Fonseca
L
L
Mazier
D
D
Rénia
L
L
D000818:Animals; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D016779:Malaria, Cerebral / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000097:blood; D010962:Plasmodium berghei / Q000276:immunology*; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D016753:Interleukin-10; D015850:Interleukin-6; D009569:Nitric Oxide; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor