Involvement of IFN-gamma receptor-mediated 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 sequestrati on in the brain, and no hemorrhages. The resistance of KO mice to ECM was a ssociated with the absence of any increases of TNF-alpha and ICAM-1 protein s 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 protei n, showed no leukocyte accumulation in the brain and this was correlated wi th the absence of ICAM-1 protein from brain microvessels. KO mice infected with 10(6) parasitized erythrocytes (PE) of Plasmodium berghei ANKA (PbA) d id 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 par asitemia than WT mice when both groups were infected with a lower dose (5x1 0(5) PE) of PbA-infected red blood cells. This indicates that different dos es of PE may trigger different IFN-gamma responses and that there may be a threshold concentration for protection against parasitemia.