Granulocyte-macrophage colony-stimulating factor-deficient mice have impaired resistance to blood-stage malaria

The contribution of granulocyte-macrophage colony-stimulating factor (GM-CS F), a hematopoietic and immunoregulatory cytokine, to resistance to blood-s tage malaria was investigated by infecting GM-CSF-deficient (knockout [KO]) mice with Plasmodium chabaudi AS. KO mice were more susceptible to infecti on than wild-type (WT) mice, as evidenced by higher peak parasitemia, recur rent recrudescent parasitemia, and high mortality. P. chabaudi AS-infected KO mice had impaired splenomegaly and lower leukocytosis but equivalent lev els of anemia compared to infected WT mice. Both bone marrow and splenic er ythropoiesis were normal in infected KO mice. However, granulocyte-macropha ge colony formation was significantly decreased in these tissues of uninfec ted and infected KO mice, and the numbers of macrophages in the spleen and peritoneal cavity were significantly lower than in infected WT mice Serum l evels of gamma interferon (IFN-gamma) were found to be significantly higher in uninfected KO mice, and the level of this cytokine was not increased du ring infection. In contrast, IFN-gamma levels were significantly above norm al levels in infected WT mice. During infection, tumor necrosis factor alph a (TNF-alpha) levels were significantly increased in KO mice and were signi ficantly higher than TNF-alpha levels in infected WT mice. Our results indi cate that GM-CSF contributes to resistance to P. chabaudi AS infection and that it is involved in the development of splenomegaly, leukocytosis, and g ranulocyte-macrophage hematopoiesis. GM-CSF may also regulate IFN-gamma and TNF-alpha production and activity in response to infection. The abnormal r esponses seen in infected KO mice may be due to the lack of GM-CSF during d evelopment, to the lack of GM-CSF in the infected mature mice, or to both.