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 Tiypanosoma 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 TNE 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.