Infection of interleukin-10 (IL-10)-nonexpressing (IL-10^−/−) mice withPlasmodium chabaudi chabaudi(AS) leads to exacerbated pathology in female mice and death in a proportion of them. Hypoglycemia, hypothermia, and loss in body weight were significantly greater in female IL-10^−/−mice than in male knockout mice and all wild-type (WT) mice during the acute phase of infection. At this time, both female and male IL-10^−/−mice produced more gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-12p40 mRNA than their respective WT counterparts. Inactivation of IFN-γ in IL-10^−/−mice by the injection of anti-IFN-γ antibodies or by the generation of IL-10^−/−IFN-γ receptor^−/−double-knockout mice resulted in reduced mortality but did not affect body weight, temperature, or blood glucose levels. The data suggest that IFN-γ-independent pathways may be responsible for these pathological features ofP. chabaudimalaria and may be due to direct stimulation of TNF-α by the parasite. Since male and female knockout mice both produce more inflammatory cytokines than their WT counterparts, it is likely that the mortality seen in females is due to the nature or magnitude of the response to these cytokines rather than the amount of IFN-γ or TNF-α produced.

Severe malaria is manifest by a variety of clinical syndromes dependent on properties of both the host and the parasite. In young infants, severe malarial anemia (SMA) is the most common syndrome of severe disease and contributes substantially to the considerable mortality and morbidity from malaria. There is now growing evidence, from both human and mouse studies of malaria, to show that anemia is due not only to increased hemolysis of infected and clearance of uninfected red blood cells (RBCs) but also to an inability of the infected host to produce an adequate erythroid response. In this review, we will summarize the recent clinical and experimental studies of malaria to highlight similarities and differences in human and mouse pathology that result in anemia and so inform the use of mouse models in the study of severe malarial anemia in humans.

The spleen is a complex organ that is perfectly adapted to selectively filtering and destroying senescent red blood cells (RBCs), infectious microorganisms and Plasmodium‐parasitized RBCs. Infection by malaria is the most common cause of spleen rupture and splenomegaly, albeit variably, a landmark of malaria infection. Here, the role of the spleen in malaria is reviewed with special emphasis in lessons learned from human infections and mouse models.

Infection with the malaria parasite, Plasmodium, is characterized by excessive inflammation. The establishment of a precise balance between the pro- and anti-inflammatory responses is critical to guarantee control of the parasite and survival of the host. IL-10, a key regulatory cytokine produced by many cells of the immune system, has been shown to protect mice against pathology during acute Plasmodium0 chabaudi chabaudi AS model of malaria. However, the critical cellular source of IL-10 is still unknown. In this article, we demonstrate that T cell-derived IL-10 is necessary for the control of pathology during acute malaria, as mice bearing specific deletion of Il10 in T cells fully reproduce the phenotype observed in Il10^−/− mice, with significant weight loss, decline in temperature, and increased mortality. Furthermore, we show that IFN-γ⁺ Th1 cells are the main producers of IL-10 throughout acute infection, expressing high levels of CD44 and ICOS, and low levels of CD127. Although Foxp3⁺ regulatory CD4⁺ T cells produce IL-10 during infection, highly activated IFN-γ⁺ Th1 cells were shown to be the essential and sufficient source of IL-10 to guarantee protection against severe immune-mediated pathology. Finally, in this model of malaria, we demonstrate that the generation of protective IL10⁺IFN-γ⁺ Th1 cells is dependent on IL-27 signaling and independent of IL-21.