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*
Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais and Centro de Pesquisas René Rachou, Oswaldo Cruz Foundation, Belo Horizonte, Brazil;
Department of Parasitology, University of Sao Paulo, Sao Paulo, Brazil;
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;
Unit for Experimental Oncology, Federal University of Sao Paulo, Sao Paulo, Brazil; and
¶ Boston University School of Medicine, Boston, MA 02118
Glycosylphosphatidylinositol (GPI) anchors and
glycoinositolphospholipids (GIPLs) from parasitic protozoa have been
shown to exert a wide variety of effects 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 GIPLs
trigger CD25 expression on Chinese hamster ovary-K1 cells transfected
with CD14 and Toll-like receptor-2 (TLR-2), but not wild-type
(TLR-2-deficient) Chinese hamster ovary cells. The protozoan-derived
GPI anchors and GIPLs containing alkylacylglycerol and saturated
fatty acid chains or ceramide were found to be active in a
concentration range of 100 nM to 1 µM. More importantly, the GPI
anchors purified from T. cruzi trypomastigotes, which
contain a longer glycan core and unsaturated fatty acids in the sn-2
position of the alkylacylglycerolipid component, triggered TLR-2 at
subnanomolar concentrations. We performed experiments with macrophages
from TLR-2 knockout and TLR-4 knockout mice, and found that TLR-2
expression appears to be essential for induction of IL-12, TNF-
, and
NO by GPI anchors derived from T. cruzi trypomastigotes.
Thus, highly purified GPI anchors from T. cruzi
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 inflammatory response during protozoan infection, and
may provide new strategies for immune intervention during protozoan
infections.
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