Tumor necrosis factor (TNF) receptor-1 (TNFp55) signal transduction and macrophage-derived soluble TNF are crucial for nitric oxide-mediated Trypanosoma congolense parasite killing.
Control of Trypanosoma congolense infections requires an early cell-mediated immune response. To unravel the role of tumor necrosis factor (TNF) in this process, 6 different T. congolense strains were used in 6 different gene-deficient mouse models that included TNF(-/-), TNF receptor-1 (TNFp55)(-/-), and TNF receptor-2 (TNFp75)(-/-) mice, 2 cell type-specific TNF(-/-) mice, as well as TNF-knock-in mice that expressed only membrane-bound TNF. Our results indicate that soluble TNF produced by macrophages/neutrophils and TNFp55 signaling are essential and sufficient to control parasitemia. The downstream mechanism in the control of T. congolense infection depends on inducible nitric oxide synthase activation in the liver. Such a role for nitric oxide is corroborated ex vivo, because the inhibitor N(G)-monomethyl-l-arginine blocks the trypanolytic activity of the adherent liver cell population, whereas exogenous interferon- gamma that stimulates nitric oxide production enhances parasite killing. In conclusion, the control of T. congolense infection depends on macrophage/neutrophil-derived soluble TNF and intact TNFp55 signaling, which induces trypanolytic nitric oxide.
Magez
Stefan
S
Department of Molecular and Cellular Recognition, Flanders Institute for Biotechnology, Brussels, Belgium. stemagez@vub.ac.be
Radwanska
Magdalena
M
Drennan
Michael
M
Fick
Lizette
L
Baral
Toya Nath
TN
Allie
Nasiema
N
Jacobs
Muazzam
M
Nedospasov
Sergei
S
Brombacher
Frank
F
Ryffel
Bernard
B
De Baetselier
Patrick
P
D000818:Animals; D002478:Cells, Cultured; D008099:Liver / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism*; D018512:Parasitemia / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction; D014348:Trypanosoma congolense / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide