A glycosylphosphatidylinositol-based treatment alleviates trypanosomiasis-associated immunopathology.
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.
Stijlemans
Benoît
B
Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussels, Pleinlaan 2, Brussels, Belgium. bstijlem@vub.ac.be
Baral
Toya Nath
TN
Guilliams
Martin
M
Brys
Lea
L
Korf
Johanna
J
Drennan
Michael
M
Van Den Abbeele
Jan
J
De Baetselier
Patrick
P
Magez
Stefan
S
D000740:Anemia / Q000628:therapy; D000818:Animals; D018949:Antigens, CD1 / Q000502:physiology; D055610:Antigens, CD1d; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D017261:Glycosylphosphatidylinositols / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000627:therapeutic use; D008231:Lymphopenia / Q000276:immunology / Q000469:parasitology / Q000628:therapy; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014346:Trypanosoma brucei brucei / Q000737:chemistry / Q000276:immunology* / Q000472:pathogenicity; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000627:therapeutic use