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 beta antibodies.
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 degrees 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-alpha) 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-alpha 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-gamma) and TNF-alpha production, indicating that other cytokines or mechanisms may be involved in their down-regulation. Significantly higher levels of transforming growth factor beta (TGF-beta), 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-gamma and TNF-alpha from the blood. Neutralization of TGF-beta in IL-10(-/-) mice resulted in higher circulating amounts of TNF-alpha and IFN-gamma, 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-beta and inflammatory cytokines such as IFN-gamma and TNF-alpha is critical for survival in a mouse malaria infection.
Li
Ching
C
Division of Parasitology, National Institute for Medical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Sanni
Latifu A
LA
Omer
Fakhreldin
F
Riley
Eleanor
E
Langhorne
Jean
J
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D005260:Female; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000097:blood; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008288:Malaria / Q000209:etiology / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009500:Neutralization Tests; D016788:Plasmodium chabaudi; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000906:Antibodies; D018836:Inflammation Mediators; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma