title: Glycosylinositolphosphate soluble variant surface glycoprotein inhibits IFN-gamma-induced nitric oxide production via reduction in STAT1 phosphorylation in African trypanosomiasis.
abstract: 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-gamma, 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-gamma vs GPI ultimately determine the macrophage response at the level of induced gene expression. Treatment of macrophages with IFN-gamma 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-alpha, IL-6, GM-CSF, and IL-12p40. In contrast, treatment of macrophages with GIP-sVSG before IFN-gamma stimulation resulted in a marked reduction of IFN-gamma-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-gamma-induced macrophage activation. These results suggest that modulation of specific aspects of the IFN-gamma response may be one mechanism by which trypanosomes overcome host resistance during African trypanosomiasis.
authors.affiliation: University of Wisconsin Medical School, Madison, WI 53706, USA.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Coller
authors.forename: John M
authors.initials: JM
authors.lastname: Mansfield
authors.forename: Donna M
authors.initials: DM
authors.lastname: Paulnock
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005260:Female; D017261:Glycosylphosphatidylinositols / Q000494:pharmacology / Q000502:physiology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D012995:Solubility; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014347:Trypanosoma brucei gambiense / Q000737:chemistry / Q000254:growth & development / Q000276:immunology; D014353:Trypanosomiasis, African / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000494:pharmacology / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D017261:Glycosylphosphatidylinositols; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C494081:Stat1 protein, rat; D015534:Trans-Activators; D014643:Variant Surface Glycoproteins, Trypanosoma; D009569:Nitric Oxide; D007371:Interferon-gamma