Interferon-gamma receptor (IFN-gamma R) deficient mice parasitized with blood-stage Plasmodium chabaudi chabaudi were used to assess the anti-malarial activity of interferon-gamma (IFN-gamma). There was no significant difference in the parasitaemia between the two types of mice during the first peak of parasitaemia. However, IFN-gamma R deficient mice displayed an increased leucocytosis and a high mortality rate, whereas all of the wild type mice survived. IFN-gamma R deficient mice, unlike wild type mice, developed a pronounced second parasitaemia peak, 9 to 11 days after the first one, with a parasitaemia of up to 65% associated with mortality. Furthermore, increased serum levels of nitric oxide (NO) were only found in wild type mice at the peak of parasitaemia, whereas it remained at background levels in IFN-gamma R deficient mice. Parasite-specific antibody production was not significantly different in IFN-gamma R deficient mice, as compared to wild type mice. In addition, both wild type and IFN-gamma R deficient mice were equally protected upon reinfection. These results indicate a delayed development of protective immunity and imply a crucial function for the IFN-gamma R in the control of blood stage malaria during the initial three weeks of infection.

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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.

Field studies of malaria in endemic areas frequently. use the presence or levels of parasitaemia, together with the measurement of fever, as the primary criteria Rlth which to identify cases. However, since malaria cases do not always present with measurable fever, and since asymptomatic parasitaemia occurs, additional episode markers might be useful epidemiological tools. We have measured the C-reactive protein and haptoglobin levels in paediatric patients presenting to a village health post in the Kilombero District in Tanzania and in convalescent sera from the same patients, in order to evaluate these acute-phase reactants as alternative markers of Plasmodium falciparum episodes. Among afebrile patients, C-reactive protein levels were highly correlated with parasite density. High C-reactive protein levels are therefore probably indicative of recent clinical malaria cpisodcs in currently afebrile individuals with high parasite densities. An appropriate case definition for malaria in epidemiological studies in endemic areas might therefore be hyperparasitaemia accompanied by either, or both, measurable fever and raised C-reactive protein levels. This would give less biased estimates of the overall burden of malaria morbidity than does a definition which requires measurable fever. Levels of haptoglobin were highly negatively correlated with parasitaemia, but did not appear to be useful episode markers because this correlation was probably not related to acute morbidity. However, haproglobin can be useful to assess at community level The impact of interventions on parasitaemia.