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J. Biol. Chem., Vol. 280, Issue 9, 8086-8093, March 4, 2005

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Spontaneous Formation of Nucleic Acid-based Nanoparticles Is Responsible for High Interferon- Induction by CpG-A in Plasmacytoid Dendritic Cells^*

Miren Kerkmann, Lilian T. Costa¶||, Christine Richter, Simon Rothenfusser, Julia Battiany, Veit Hornung, Judith Johnson**, Steffen Englert, Thomas Ketterer, Wolfgang Heckl¶, Stefan Thalhammer¶||, Stefan Endres, and Gunther Hartmann¶¶

From the Department of Internal Medicine, Division of Clinical Pharmacology, Ludwig-Maximilians-University of Munich, 80336 Muenchen, Germany, ^¶Department of Geo- and Environment Sciences, Ludwig-Maximilians-University of Munich, 80333 Muenchen, Germany, ^**Institute of Immunology, Ludwig-Maximilians-University of Munich, 80336 Muenchen, Germany, CureVac GmbH, 72076 Tuebingen, Germany, and Research Center for Nucleic Acid and Peptide Chemistry, University of Tuebingen, 72076 Tuebingen, Germany

Plasmacytoid dendritic cells (PDC) represent a highly specialized immune cell subset that produces large quantities of the anti-viral cytokines type I interferons (IFN- and IFN-) upon viral infection. PDC employ a member of the family of toll-like receptors, TLR9, to detect CpG motifs (unmethylated CG dinucleotides in certain base context) present in viral DNA. A certain group of CpG motif-containing oligodeoxynucleotides (CpG ODN), CpG-A, was the first synthetic stimulus available that induced large amounts of interferon- (IFN-) in PDC. However, the mechanism responsible for this activity remained elusive. CpG-A is characterized by a central palindrome and poly(G) at the 5' and 3' end. Here we demonstrate that CpG-A self-assembles to higher order tertiary structures via G-tetrad formation of their poly(G) motifs. Spontaneous G-tetrad formation of CpG-A required the palindrome sequence allowing structure formation in a physiological environment. Once formed, G-tetrad-linked structures were stable even under denaturing conditions. Atomic force microscopy revealed that the tertiary structures formed by CpG-A represent nucleic acid-based nanoparticles in the size range of viruses. Similarly sized preformed polystyrene nanoparticles loaded with a CpG ODN that is otherwise weak at inducing IFN- (CpG-B) gained the potency of CpG-A to induce IFN-. Higher ODN uptake in PDC was not responsible for the higher IFN--inducing activity of CpG-A or of CpG-B-coated nanoparticles as compared with CpG-B. Based on these results we propose a model in which the spatial configuration of CpG motifs as particle is responsible for the virus-like potency of CpG-A to induce IFN- in PDC.

Received for publication, September 21, 2004 , and in revised form, December 3, 2004.

^* This study was supported in part by a grant from the Bundesministerium für Bildung und Forschung (Biofuture 0311896), Deutsche Forschungsgemeinschaft Grants HA 2780/4-1 and SFB 571, Dr. Mildred Scheel Stiftung Grant 10-2074, and a grant from the Human Science Foundation of Japan (to G. H.). 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.

This work is part of the dissertation of this author at the Ludwig-Maximilians-University of Munich.

^|| Financially supported by the Deutscher Akademischer Austauschdienst and Deutsche Forschungsgemeinschaft Sonderforschungsbereich 486.

^¶¶ To whom correspondence should be addressed: Abteilung für Klinische Pharmakologie, Medizinische Klinik Innenstadt, Klinikum der Ludwig-Maximilians-Universität München, Ziemssenstrasse 1, 80336 München, Germany. Tel.: 49-89-5160-2331; Fax: 49-89-5160-4406; E-mail: ghartmann{at}lrz.uni-muenchen.de.

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