Activation of toll-like receptor-2 by glycosylphosphatidylinositol anchorsfrom a protozoan parasite

Glycosylphosphatidylinositol (GPI) anchors and glycoinositolphospholipids ( GIPLs) from parasitic protozoa have been shown to exert a wide variety of e ffects on cells of the host innate immune system. However, the receptor(s) that are triggered by these protozoan glycolipids has not been identified. Here we present evidence that Trypanosoma cruzi-derived GPI anchors and GIP Ls trigger CD25 expression on Chinese hamster ovary-KI cells transfected wi th CD14 and Toll-like receptor-2 (TLR-2), but not wild-type (TLR-2-deficien t) Chinese hamster ovary cells. The protozoan-derived GPI anchors and GIPLs containing alkylacyl-glycerol and saturated fatty acid chains or ceramide were found to be active in a concentration range of 100 nM to 1 muM. More i mportantly, the GPI anchors purified from T. cruzi trypomastigotes, which c ontain a longer glycan core and unsaturated fatty acids in the sn-2 positio n of the alkylacylglycerolipid component, triggered TLR-2 at subnanomolar c oncentrations. We performed experiments with macrophages from TLR-2 knockou t and TLR-4 knockout mice, and found that TLR-2 expression appears to be es sential for induction of IL-12, TNF-alpha, and NO by GPI anchors derived fr om T. cruzi trypomastigotes. Thus, highly purified GPI anchors from T. cruz i parasites are potent activators of TLR-2 from both mouse and human origin . The activation of TLR-2 may initiate host innate defense mechanisms and i nflammatory response during protozoan infection, and may provide new strate gies for immune intervention during protozoan infections. The Journal of Im munology, 2001.