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TLR9 Contributes to Antiviral Immunity during Gammaherpesvirus Infection¹

Simone Guggemoos^*, Doris Hangel, Svetlana Hamm, Antje Heit, Stefan Bauer and Heiko Adler^2,*

^* Institute of Molecular Immunology, Clinical Cooperation Group Hematopoietic Cell Transplantation, GSF-National Research Center for Environment and Health, Munich, Germany; Institute of Medical Microbiology, Immunology and Hygiene, Technical University, Munich, Germany; and Institute of Immunology, University Marburg, Marburg, Germany

The human gammaherpesviruses Kaposi’s sarcoma-associated herpesvirus and EBV cause important infections. As pathogenetic studies of the human infections are restricted, murine gammaherpesvirus 68 serves as a model to study gammaherpesvirus pathogenesis. TLRs are a conserved family of receptors detecting microbial molecular patterns. Among the TLRs, TLR9 recognizes unmethylated CpG DNA motifs present in bacterial and viral DNA. The aim of this study was to assess the role of TLR9 in gammaherpesvirus pathogenesis. Upon stimulation with murine gammaherpesvirus 68, Flt3L-cultured bone marrow cells (dendritic cells) from TLR9^–/– mice secreted reduced levels of IL-12, IFN-, and IL-6, when compared with dendritic cells from wild-type mice. Intranasal infection of TLR9^–/– and wild-type mice did not reveal any differences during lytic and latent infection. In contrast, when infected i.p., TLR9^–/– mice showed markedly higher viral loads both during lytic and latent infection. Thus, we show for the first time that TLR9 is involved in gammaherpesvirus pathogenesis and contributes to organ-specific immunity.

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 grants from the Deutsche Forschungsgemeinschaft (DFG; Ad121/2-1, 2-2, and 2-4) and the Bundesministerium für Bildung und Forschung (NGFN-2, FKZ 01GS0405) to H.A., and the DFG Schwerpunktprogramm 1110 "Innate Immunity" to S.B.

² Address correspondence and reprint requests to Dr. Heiko Adler, Institute of Molecular Immunology, Clinical Cooperation Group Hematopoietic Cell Transplantation, GSF-National Research Center for Environment and Health, Marchioninistrasse 25, D-81377 Munich, Germany. E-mail address: h.adler{at}gsf.de

³ Abbreviations used in this paper: MHV-68, murine gammaherpesvirus 68; MCMV, murine CMV; DC, dendritic cell; FL-DC, Flt3L-cultured bone marrow cell; i.n., intranasal; BHK, baby hamster kidney cell; wt, wild type; pDC, plasmacytoid DC; MOI, multiplicity of infection; gB, glycoprotein B; p.i., postinfection.