Both lymphotoxin-alpha and TNF are crucial for control of Toxoplasma gondii in the central nervous system.
Immunity to Toxoplasma gondii critically depends on TNFR type I-mediated immune reactions, but the precise role of the individual ligands of TNFR1, TNF and lymphotoxin-alpha (LTalpha), is still unknown. Upon oral infection with T. gondii, TNF(-/-), LTalpha(-/-), and TNF/LTalpha(-/-) mice failed to control intracerebral T. gondii and succumbed to an acute necrotizing Toxoplasma encephalitis, whereas wild-type (WT) mice survived. Intracerebral inducible NO synthase expression and-early after infection-splenic NO levels were reduced. Additionally, peritoneal macrophages produced reduced levels of NO upon infection with T. gondii and had significantly reduced toxoplasmastatic activity in TNF(-/-), LTalpha(-/-), and TNF/LTalpha(-/-) mice as compared with WT animals. Frequencies of parasite-specific IFN-gamma-producing T cells, intracerebral and splenic IFN-gamma production, and T. gondii-specific IgM and IgG titers in LTalpha(-/-) and TNF/LTalpha(-/-) mice were reduced only early after infection. In contrast, intracerebral IL-10 and IL-12p40 mRNA expression and splenic IL-2, IL-4, and IL-12 production were identical in all genotypes. In addition, TNF(-/-), LTalpha(-/-), and TNF/LTalpha(-/-), but not WT, mice succumbed to infection with the highly attenuated ts-4 strain of T. gondii or to a subsequent challenge infection with virulent RH toxoplasms, although they had identical frequencies of IFN-gamma-producing T cells as compared with WT mice. Generation and infection of bone marrow reconstitution chimeras demonstrated an exclusive role of hematogeneously produced TNF and LTalpha for survival of toxoplasmosis. These findings demonstrate the crucial role of both LTalpha and TNF for control of intracerebral toxoplasms.
Schlüter
Dirk
D
Institut für Medizinische Mikrobiologie und Hygiene and Zentrum für Medizinische Forschung, Universitätsklinikum Mannheim, Universität Heidelberg, Mannheim, Germany.
Kwok
Lai-Yu
LY
Lütjen
Sonja
S
Soltek
Sabine
S
Hoffmann
Sigrid
S
Körner
Heinrich
H
Deckert
Martina
M
D000208:Acute Disease; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis; D000918:Antibody Specificity / Q000235:genetics; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D016207:Cytokines / Q000096:biosynthesis; D004660:Encephalitis / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D006579:Heterozygote; D018655:Lymphocyte Count; D008233:Lymphotoxin-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016052:Protozoan Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology / Q000469:parasitology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D014122:Toxoplasma / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D016781:Toxoplasmosis, Cerebral / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000913:Antibodies, Protozoan; D016207:Cytokines; D008233:Lymphotoxin-alpha; D016052:Protozoan Vaccines; D014409:Tumor Necrosis Factor-alpha