23 Activation of Toll-Like Receptors 2 and 6 Heterodimer by Synthetic Trypanosoma Cruzi Trypomastigote Glycosylphosphatidylinositols Is Enhanced by Coexpression of CD14 and CD36

Wednesday, November 4, 2009
Ballroom A+B (Camino Real Hotel)
Lilian L. Nohara, PharmB , Dept. of Biological Sciences, The Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX
Dmitry Yashunsky, PhD , Division of Biological Chemistry and Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, United Kingdom
Michael AJ Ferguson, PhD , Division of Biological Chemistry and Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, United Kingdom
Andrei V Nikolaev , Division of Biological Chemistry and Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, United Kingdom
Igor C. Almeida, DSc , Dept. of Biological Sciences, The Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX
Glycosylphosphatidylinositol (GPI)-anchored glycoconjugates are major surface antigens of pathogenic protozoan parasites, including Trypanosoma cruzi, the causative agent of Chagas disease (CD), which affects millions of people in the American continent. We have previously shown that GPI anchors purified from T. cruzi trypomastigote mucins (tGPIs) are potent proinflammatory agents, and proposed that tGPIs play important roles in host resistance and tissue inflammatory responses related to CD pathogenesis. To clarify the structural traits responsible for the tGPI proinflammatory activity, tGPIs containing sn1-O-(C16:0)-alkyl-2-O-(C18:1, C18:2, or C16:0)-acylglycerol lipid were chemically synthesized. Here, we demonstrate that these synthetic tGPIs (stGPIs) are biologically active. We provide the first clear evidence that stGPIs are preferentially recognized by the Toll-like receptors 2 and 6 heterodimer (TLR2/6) and that CD14 expression leads to enhanced responses assessed as NF-kB activation and IL-8 production by cells transfected with distinct TLRs and coreceptors. We also show that CD36, a transmembrane glycoprotein implicated in innate immune responses to pathogens, collaborates with TLR2/6 and CD14 in the proinflammatory responses by tGPIs. Although the TLR and coreceptor requirements of stGPIs with different lipid moieties are similar, our data indicate that stGPIs containing unsaturated (C18:1 or C18:2) fatty acid induce a much stronger response as compared to the saturated (C16:0) fatty acid-containing stGPI. This result confirms previous predictions that the presence of unsaturated fatty acid may be responsible for the higher activity induced by tGPIs. Funding: NIH grants RO1AI070655 and 5G12RR008124, The Wellcome Trust, and Cotton Memorial, Good Neighbor and Florence Terry-Griswold Scholarships.
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