|Title||A glycosylphosphatidylinositol-based treatment alleviates trypanosomiasis-associated immunopathology.|
|Publication Type||Journal Article|
|Year of Publication||2007|
|Authors||Stijlemans, B., T. Nath Baral, M. Guilliams, L. Brys, J. Korf, M. Drennan, J. Van Den Abbeele, P. De Baetselier, and S. Magez|
|Date Published||2007 Sep 15|
|Keywords||Anemia, Animals, Antigens, CD1, Antigens, CD1d, B-Lymphocyte Subsets, Disease Models, Animal, Glycosylphosphatidylinositols, Inflammation Mediators, Lymphopenia, Macrophage Activation, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction, Trypanosoma brucei brucei, Trypanosomiasis, African, Variant Surface Glycoproteins, Trypanosoma|
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.
|Alternate Journal||J. Immunol.|