Pathology of Plasmodium chabaudi chabaudi Infection and Mortality in Interleukin-10-Deficient Mice Are Ameliorated by Anti-Tumor Necrosis Factor Alpha and Exacerbated by Anti-Transforming Growth Factor β Antibodies

Abstract

ABSTRACT Interleukin-10 (IL-10)-deficient (IL-10 −/− ) mice infected with Plasmodium chabaudi (AS) suffer a more severe disease and exhibit a higher rate of mortality than control C57BL/6 mice. Here, we show that a drop in body temperature to below 28°C and pronounced hypoglycemia of below 3 mM are reliable indicators of a lethal infection. Elevated inflammatory responses have been shown to accompany pathology in infected IL-10 −/− mice. We show that neutralization of tumor necrosis factor alpha (TNF-α) in IL-10 −/− mice abolishes mortality and ameliorates the hypothermia, weight loss, and anemia but does not affect the degree of hypoglycemia. These data suggest that TNF-α is involved in some of the pathology associated with a P. chabaudi infection in IL-10 −/− mice but other factors play a role. IL-10 −/− mice that survive a primary infection have been shown to control gamma interferon (IFN-γ) and TNF-α production, indicating that other cytokines or mechanisms may be involved in their down-regulation. Significantly higher levels of transforming growth factor β (TGF-β), a cytokine with such properties, are present in the plasma of infected IL-10 −/− mice at a time that coincides with the disappearance of IFN-γ and TNF-α from the blood. Neutralization of TGF-β in IL-10 −/− mice resulted in higher circulating amounts of TNF-α and IFN-γ, and all treated IL-10 −/− mice died within 12 days with increased pathology but with no obvious increase in parasitemia. Our data suggest that a tight regulation of the balance between regulatory cytokines such as IL-10 and TGF-β and inflammatory cytokines such as IFN-γ and TNF-α is critical for survival in a mouse malaria infection.