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Smallpox Inhibitor of Complement Enzymes (SPICE): Regulation of Complement Activation on Cells and Mechanism of Its Cellular Attachment¹

M. Kathryn Liszewski^2,*, Paula Bertram^2,*, Marilyn K. Leung^*, Richard Hauhart^*, Lijuan Zhang and John P. Atkinson^3,*

^* Department of Medicine/Division of Rheumatology and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

Despite eradication of smallpox three decades ago, public health concerns remain due to its potential use as a bioterrorist weapon. Smallpox and other orthopoxviruses express virulence factors that inhibit the host’s complement system. In this study, our goals were to characterize the ability of the smallpox inhibitor of complement enzymes, SPICE, to regulate human complement on the cell surface. We demonstrate that SPICE binds to a variety of cell types and that the heparan sulfate and chondroitin sulfate glycosaminoglycans serve as attachment sites. A transmembrane-engineered version as well as soluble recombinant SPICE inhibited complement activation at the C3 convertase step with equal or greater efficiency than that of the related host regulators. Moreover, SPICE attached to glycosaminoglycans was more efficient than transmembrane SPICE. We also demonstrate that this virulence activity of SPICE on cells could be blocked by a mAb to SPICE. These results provide insights related to the complement inhibitory activities of poxviral inhibitors of complement and describe a mAb with therapeutic potential.

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 National Institutes of Health Grant U54 AI057160 to the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (MRCE). Work performed at the High Speed Cell Sorter Core at the Siteman Cancer Center at Washington University is supported in part by National Cancer Institute Cancer Center Support Grant P30 CA91842.

² M.K.L. and P.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. John P. Atkinson, Department of Medicine/Division of Rheumatology, Washington University School of Medicine, Campus Box 8045, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: jatkinso{at}im.wustl.edu

⁴ Abbreviations used in this paper: PICES, poxviral inhibitors of complement enzymes; CCP, complement control protein; CHO, Chinese hamster ovary (cells); CS, chondroitin sulfate; DAA, decay accelerating activity; DAF, decays accelerating factor (CD55); GAG, glycosaminoglycan; GVB, gelatin veronal-buffered saline; HS, heparan sulfate; MCP, membrane cofactor protein (CD46); MFI, mean fluorescence intensity; MOPICE, monkeypox inhibitor of complement enzymes; SPICE, smallpox inhibitor of complement enzymes; SPICE-TM, transmembrane SPICE; VCP, vaccinia complement control protein.

This article has been cited by other articles:

				M. K. Liszewski, M. K. Leung, R. Hauhart, C. J. Fang, P. Bertram, and J. P. Atkinson Smallpox Inhibitor of Complement Enzymes (SPICE): Dissecting Functional Sites and Abrogating Activity J. Immunol., September 1, 2009; 183(5): 3150 - 3159. [Abstract] [Full Text] [PDF]