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Infection and Immunity, September 2003, p. 4850-4856, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.4850-4856.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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 ß Antibodies

Ching Li,1 Latifu A. Sanni,1 Fakhreldin Omer,2 Eleanor Riley,2 and Jean Langhorne1*

Division of Parasitology, National Institute for Medical Research,1 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom2

Received 4 February 2003/ Returned for modification 7 March 2003/ Accepted 27 May 2003

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-{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 ß (TGF-ß), 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-ß 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-ß and inflammatory cytokines such as IFN-{gamma} and TNF-{alpha} is critical for survival in a mouse malaria infection.

* Corresponding author. Mailing address: Division of Parasitology, National Institute for Medical Research, The Ridgeway, London NW7 1AA, United Kingdom. Phone: 44 0 20 8959 3666. Fax: 44 0 20 8816 2638. E-mail: jlangho{at}nimr.mrc.ac.uk.

Editor: J. M. Mansfield

Infection and Immunity, September 2003, p. 4850-4856, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.4850-4856.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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