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Infect Immun, June 1998, p. 2960-2968, Vol. 66, No. 6
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Trypanosoma cruzi Infection in Tumor Necrosis Factor Receptor p55-Deficient Mice

Esmeralda Castaños-Velez,1 Stephanie Maerlan,2 Lyda M. Osorio,2 Frederik Åberg,3 Peter Biberfeld,1 Anders Örn,2 and Martín E. Rottenberg2,*

Department of Pathology,1 Microbiology and Tumorbiology Center,2 and Department of Neurosciences,3 Karolinska Institute, Stockholm, Sweden

Received 15 October 1997/Returned for modification 15 December 1997/Accepted 18 March 1998

Tumor necrosis factor receptor p55 (TNFRp55) mediates host resistance to several pathogens by allowing microbicidal activities of phagocytes. In the studies reported here, TNFRp55-/- mice infected with the intracellular parasite Trypanosoma cruzi showed clearly higher parasitemia and cumulative mortality than wild-type (WT) controls did. However, gamma interferon (IFN-gamma )-activated macrophages from TNFRp55-/- mice produced control levels of nitric oxide and killed the parasite efficiently in vitro. Trypanocidal mechanisms of nonphagocytic cells (myocardial fibroblasts) from both TNFRp55-/- and WT mice were also activated by IFN-gamma in a dose-dependent way. However, IFN-gamma -activated TNFRp55-/- nonphagocytes showed less effective killing of T. cruzi than WT control nonphagocytes, even when interleukin 1beta (IL-1beta ) was added as a costimulator. In vivo, T. cruzi-infected TNFRp55-/- mice and WT mice released similar levels of NO and showed similar levels of IFN-gamma mRNA and inducible nitric oxide synthase mRNA in their tissues. Instead, increased susceptibility to T. cruzi of TNFRp55-/- mice was associated with reduced levels of parasite-specific immunoglobulin G (IgG) (but not IgM) antibodies during infection, which is probably linked to abnormal B-cell differentiation in secondary lymphoid tissues of the mutant mice. Surprisingly, T. cruzi-infected TNFRp55-/- mice showed increased inflammatory and necrotic lesions in several tissues, especially in skeletal muscles, indicating that TNFRp55 plays an important role in controlling the inflammatory process. Accordingly, levels of Mn2+ superoxide dismutase mRNA, a TNF-induced enzyme which protects the cell from the toxic effects of superoxide, were lower in mutant than in WT infected mice.

* Corresponding author. Mailing address: Microbiology & Tumorbiology Center, Karolinska Institute, Box 280, 171 77 Stockholm, Sweden. Phone: 46-8-728-6232. Fax: 46-8-32-8878. E-mail: Martin.Rottenberg{at}mtc.ki.se.

Infect Immun, June 1998, p. 2960-2968, Vol. 66, No. 6
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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