title: Trypanosoma cruzi infection in tumor necrosis factor receptor p55-deficient mice.
abstract: 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.
authors.affiliation: Department of Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Castaños-Velez
authors.forename: S
authors.initials: S
authors.lastname: Maerlan
authors.forename: L M
authors.initials: LM
authors.lastname: Osorio
authors.forename: F
authors.initials: F
authors.lastname: Aberg
authors.forename: P
authors.initials: P
authors.lastname: Biberfeld
authors.forename: A
authors.initials: A
authors.lastname: Orn
authors.forename: M E
authors.initials: ME
authors.lastname: Rottenberg
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D015703:Antigens, CD / Q000378:metabolism*; D014355:Chagas Disease / Q000276:immunology* / Q000401:mortality; D004198:Disease Susceptibility; D005347:Fibroblasts / Q000276:immunology / Q000469:parasitology; D006321:Heart / Q000469:parasitology; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007371:Interferon-gamma / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000166:cytology; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D018512:Parasitemia / Q000276:immunology* / Q000401:mortality; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D013154:Spleen / Q000473:pathology; D013482:Superoxide Dismutase / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000913:Antibodies, Protozoan; D015703:Antigens, CD; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D009566:Nitrates; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013482:Superoxide Dismutase