title: Interferon-gamma receptor-deficiency renders mice highly susceptible to toxoplasmosis by decreased macrophage activation.
abstract: Toxoplasma gondii may cause severe infections in immunocompromised patients including fetuses and those with AIDS. Among the factors mediating protection against T. gondii, IFN-gamma has gained special attention. To analyze the role of IFN-gamma in the early phase of toxoplasmosis, IFN-gamma receptor-deficient (IFN-gamma R0/0) mice were orally infected with low-virulent toxoplasms. IFN-gamma R0/0 mice died of the disease up to day 10 postinfection, whereas immunocompetent wild-type (WT) mice developed a chronic toxoplasmosis. Histopathology revealed that in IFN-gamma R0/0 mice, the parasite multiplied unrestrictedly in the small intestine, the intestinal lymphatic tissue, the liver, and the spleen. Ultimately, animals died of a necrotizing hepatitis. In WT mice, the same organs were effected, but multiplication of the parasite was effectively limited. Compared with WT mice, immunohistochemistry and flow cytometry demonstrated that in IFN-gamma R0/0 mice, macrophages were only marginally activated in response to the infection, as evidenced by a reduced expression of major histocompatability complex class II antigens. In addition, immunohistochemistry and RT-PCR showed a reduced production of the macrophage-derived cytokines tumor necrosis factor-alpha, inducible nitric oxide synthase, and IL-1 beta in the liver of IFN-gamma R0/0 mice. In contrast, activation of T cells, recruitment of immune cells to inflammatory foci, and anti-T. gondii IgM antibody production were unaffected by the mutation of the IFN-gamma R. Moreover, induction of IL-2, IL-4, and IL-10 mRNA transcripts in the liver was normal in IFN-gamma R0/0 mice. Adoptive transfer experiments revealed that the immune T cells of WT animals did not protect IFN-gamma R0/0 mice from lethal infection with highly virulent toxoplasms, whereas WT mice were significantly protected by the adoptive transfer. Based on these studies, we conclude that IFN-gamma is absolutely required for an efficient activation of macrophages. Macrophages are of critical importance in toxoplasmosis, and insufficient macrophage activation cannot be compensated by other immune mechanisms.
authors.affiliation: Institut für Neuropathologie, Universitätskliniken Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Deckert-Schlüter
authors.forename: A
authors.initials: A
authors.lastname: Rang
authors.forename: D
authors.initials: D
authors.lastname: Weiner
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.forename: O D
authors.initials: OD
authors.lastname: Wiestler
authors.forename: H
authors.initials: H
authors.lastname: Hof
authors.forename: D
authors.initials: D
authors.lastname: Schlüter
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis*; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007421:Intestine, Small / Q000469:parasitology / Q000473:pathology; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D017471:Receptors, Interferon / Q000235:genetics* / Q000502:physiology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D014122:Toxoplasma / Q000276:immunology / Q000302:isolation & purification / Q000472:pathogenicity; D014124:Toxoplasmosis, Animal / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014158:Transcription, Genetic; D014774:Virulence; D000096743:Interferon gamma Receptor
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D019001:Nitric Oxide Synthase; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor