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Infection and Immunity, July 2000, p. 4075-4083, Vol. 68, No. 7
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Tumor Necrosis Factor Alpha-Mediated Toxic Shock in Trypanosoma cruzi-Infected Interleukin 10-Deficient Mice

Christoph Hölscher,1,dagger Markus Mohrs,1,Dagger Wen Juan Dai,1,§ Gabriele Köhler,2 Bernhard Ryffel,3 Günter A. Schaub,4 Horst Mossmann,1 and Frank Brombacher3,*

Max-Planck-Institute for Immunobiology1 and Department of Pathology, University of Freiburg,2 Freiburg, and Department of Special Zoology and Parasitology, University of Bochum, Bochum,4 Germany, and Department of Immunology, University of Cape Town, Cape Town, South Africa3

Received 7 September 1999/Returned for modification 23 November 1999/Accepted 30 March 2000

Using interleukin-10 (IL-10)-deficient (IL-10-/-) mice, previous studies revealed a pathological immune response after infection with Trypanosoma cruzi that is associated with CD4+ T cells and overproduction of proinflammatory cytokines. In this study we further investigate the pathology and potential mediators for the mortality in infected animals. T. cruzi-infected IL-10-/- mice showed reduced parasitemia accompanied by increased systemic release of gamma interferon (IFN-gamma ), IL-12, and reactive nitrogen intermediates and overproduction of tumor necrosis factor alpha (TNF-alpha ). Despite this early resistance, IL-10-/- mice died within the third week of infection, whereas all control mice survived acute infection. The clinical manifestation with weight loss, hypothermia, hypoglycemia, hyperkalemia, and increased liver-derived enzymes in the blood together with hepatic necrosis and intravascular coagulation in moribund mice indicated a toxic shock-like syndrome, possibly mediated by the systemic TNF-alpha overproduction. Indeed, high production of systemic TNF-alpha significantly correlated with mortality, and moribund mice died with critically high TNF-alpha concentrations in the blood. Consequent treatment with anti-TNF-alpha antiserum attenuated pathological changes in T. cruzi-infected IL-10-/- mice and significantly prolonged survival; the mice died during the fourth week postinfection, again with a striking correlation between regaining high systemic TNF-alpha concentrations and the time of death. Since elevated serum IL-12 and IFN-gamma concentrations were not affected by the administration of antiserum, these studies suggest that TNF-alpha is the direct mediator of this toxic shock syndrome. In conclusion, induction of endogenous IL-10 during experimentally induced Chagas' disease seems to be crucial for counterregulating an overshooting proinflammatory cytokine response resulting in TNF-alpha -mediated toxic shock.

* Corresponding author. Mailing address: Department of Immunology, University of Cape Town, Groote Schuur Hospital, OMB H47, Observatory 7925, South Africa. Phone: 27-21-404-4013. Fax: 27-21-448-6116. E-mail: fbrombac{at}uctgsh1.uct.ac.za.

dagger Present address: Department of Immunology, University of Cape Town, Cape Town, South Africa.

Dagger Present address: Department of Microbiology and Immunology, University of California---San Francisco, San Francisco, Calif.

§ Present address: Institute for Veterinary Pathology, University of Bern, Bern, Switzerland.

Infection and Immunity, July 2000, p. 4075-4083, Vol. 68, No. 7
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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