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The Soluble Variant Surface Glycoprotein of African Trypanosomes Is Recognized by a Macrophage Scavenger Receptor and Induces IB Degradation Independently of TRAF6-Mediated TLR Signaling¹

Brian J. Leppert^*, John M. Mansfield and Donna M. Paulnock^2,*

^* Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706; and Department of Bacteriology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706

The GPI residues of soluble variant surface glycoprotein (sVSG) molecules released from the membrane of African trypanosomes during infection induce macrophage activation events. In this study, we demonstrate that the trypanosome sVSG molecule binds to the membrane of murine RAW 264.7 macrophages and activates the NF-B cascade independently of a TLR-mediated interaction. The binding of fluorochrome-labeled sVSG molecules to macrophage membranes was saturable, was inhibited by the scavenger receptor-specific ligand maleylated BSA, and was followed by rapid intracellular uptake of the molecules and subsequent internalization to lysosomal compartments. Inhibition of cellular phagocytic and endocytic uptake processes by cytochalasin B and monodansylcadaverine, respectively, revealed that sVSG internalization was necessary for IB degradation and occurred by an actin-dependent, clathrin-independent process. Activation of RAW 264.7 cells by sVSG following treatment of the cells with the TRAF6 inhibitory peptide DIVK resulted in enhanced NF-B signaling, suggesting both that TRAF6-dependent TLR activation of the pathway alone is not required for signaling and that TLR pathway components may negatively regulate expression of sVSG-induced signaling. These results demonstrate that stimulation of macrophages by sVSG involves a complex process of receptor-mediated binding and uptake steps, leading to both positive and negative signaling events that ultimately regulate cellular activation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by U.S. Public Health Service Grants AI-048242 and AI-051421 (to D.M.P.).

² Address correspondence and reprint requests to Dr. Donna M. Paulnock, Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53706. E-mail address: paulnock{at}wisc.edu

³ Abbreviations used in this paper: PRR, pattern-recognition receptor; VSG, variant surface glycoprotein; sVSG, soluble VSG; TRAF6, TNFR-associated factor 6; OG, Oregon Green; SR, scavenger receptor; mBSA, maleylated BSA; TFA, trifluoroacetic acid; BMM, bone marrow-derived macrophage.

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