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-Induced Nitric Oxide Production Via Reduction in STAT1 Phosphorylation in African Trypanosomiasis1
University of Wisconsin Medical School, Madison, WI 53706
Macrophages are centrally involved in the host immune response to infection with Trypanosoma brucei rhodesiense, a protozoan parasite responsible for human sleeping sickness in Africa. During trypanosome infections, the host is exposed to parasite-derived molecules that mediate macrophage activation, specifically GPI anchor substituents associated with the shed variant surface glycoprotein (VSG), plus the host-activating agent IFN-
, which is derived from activated T cells and is essential for resistance to trypanosomes. In this study, we demonstrate that the level and timing of exposure of macrophages to IFN- vs GPI ultimately determine the macrophage response at the level of induced gene expression. Treatment of macrophages with IFN- followed by GIP-sVSG (the soluble form of VSG containing the glycosylinositolphosphate substituent that is released by parasites) stimulated the induction of gene expression, including transcription of TNF-
, IL-6, GM-CSF, and IL-12p40. In contrast, treatment of macrophages with GIP-sVSG before IFN- stimulation resulted in a marked reduction of IFN--induced responses, including transcription of inducible NO synthase and secretion of NO. Additional experiments revealed that the inhibitory activity of GIP-sVSG was associated with reduction in the level of STAT1 phosphorylation, an event required for IFN--induced macrophage activation. These results suggest that modulation of specific aspects of the IFN- response may be one mechanism by which trypanosomes overcome host resistance during African trypanosomiasis.
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