A Glycosylphosphatidylinositol-Based Treatment Alleviates Trypanosomiasis-Associated Immunopathology

Abstract

The GPI-anchored trypanosome variant surface glycoprotein (VSG) triggers macrophages to produce TNF, involved in trypanosomiasis-associated inflammation and the clinical manifestation of sleeping sickness. Aiming at inhibiting immunopathology during experimental Trypanosoma brucei infections, a VSG-derived GPI-based treatment approach was developed. To achieve this, mice were exposed to the GPI before an infectious trypanosome challenge. This GPI-based strategy resulted in a significant prolonged survival and a substantial protection against infection-associated weight loss, liver damage, acidosis, and anemia; the latter was shown to be Ab-independent and correlated with reduced macrophage-mediated RBC clearance. In addition, GPI-based treatment resulted in reduced circulating serum levels of the inflammatory cytokines TNF and IL-6, abrogation of infection-induced LPS hypersensitivity, and an increase in circulating IL-10. At the level of trypanosomiasis-associated macrophage activation, the GPI-based treatment resulted in an impaired secretion of TNF by VSG and LPS pulsed macrophages, a reduced expression of the inflammatory cytokine genes TNF, IL-6, and IL-12, and an increased expression of the anti-inflammatory cytokine gene IL-10. In addition, this change in cytokine pattern upon GPI-based treatment was associated with the expression of alternatively activated macrophage markers. Finally, the GPI-based treatment also reduced the infection-associated pathology in Trypanosoma congolense and Trypanosoma evansi model systems as well as in tsetse fly challenge experiments, indicating potential field applicability for this intervention strategy.

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

“…The supernatant was dialyzed against 10 mM Tris, pH 7.4, and the sVSG was purified using ion-exchange chromatography and gel filtration as described previously [79,80]. mfVSG was prepared as described previously [81]. Prior to performing a size exclusion chromatography (equilibrated against 10 mM Tris, pH 7.4, containing 0.02% N-octylglucoside, Sigma-Aldrich), the mfVSG was treated with benzonase (similar as for sVSG) to remove potential nucleic acid contamination.…”

Host-Parasite Interactions in Trypanosomiasis: on the Way to an Antidisease Strategy

“…The important role of GIP as a pathogenesis-inducing factor has led to trials consisting of the treatment of mice with GIP molecules before infection (145). These trials were successful in reducing weight loss, liver damage, acidosis, and anemia during infections by T. brucei.…”

IL-10 Dampens TNF/Inducible Nitric Oxide Synthase-Producing Dendritic Cell-Mediated Pathogenicity during Parasitic Infection

“…On the other side, a particular subset of MHC-II-restricted socalled "pathogenic" CD4 ϩ T cells producing IFN-␥ has been suggested to contribute to early mortality of infected hosts (11). However, although the major source of TNF and NO is thought to be classically activated monocytic cells (M1) (10,17), the exact cellular origin of these pathogenic M1 cells has not been formally identified. Therefore, *Department of Molecular and Cellular Interactions, VIB, Brussels, Belgium; † Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; in this study, we have scrutinized the phenotype of monocytic cells producing TNF and NO in T. brucei brucei-infected mice.…”