A defect in interleukin-10 leads to enhanced malarial disease in Plasmodium chabaudi chabaudi infection in mice

Infection of interleukin-10 (IL-10)-nonexpressing (IL-10(-/-)) mice with Pl asmodium chabaudi chabaudi (AS) leads to exacerbated pathology in female mi ce and death in a proportion of them. Hypoglycemia, hypothermia, and loss i n 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 in fection. At this time, both female and male IL-10(-/-) mice produced more g amma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and I L-12p40 mRNA than their respective WT counterparts. Inactivation of IFN-gam ma in IL-10(-/-) mice by the injection of anti-IFN-gamma antibodies or by t he generation of IL-10(-/-) IFN-gamma receptor(-/-) double-knockout mice re sulted in reduced mortality but did not affect body weight, temperature, or blood glucose levels. The data suggest that IFN-gamma-independent pathways may be responsible for these pathological features of P. chabaudi malaria and may be due to direct stimulation of TNF-alpha by the parasite. Since ma le and female knockout mice both produce more inflammatory cytokines than t heir WT counterparts, it is likely that the mortality seen in females is du e to the nature or magnitude of the response to these cytokines rather than the amount of IFN-gamma or TNF-alpha produced.