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Journal of Virology, September 2009, p. 9411-9422, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.02362-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Conventional Bone Marrow-Derived Dendritic Cells Contribute to Toll-Like Receptor-Independent Production of Alpha/Beta Interferon in Response to Inactivated Parapoxvirus Ovis{triangledown}

Sabine Siegemund,1,# Andrea Hartl,2 Heiner von Buttlar,1 Franziska Dautel,1,{dagger} Rüdiger Raue,3 Marina A. Freudenberg,4 György Fejer,4 Mathias Büttner,5 Gabriele Köhler,6 Carsten J. Kirschning,2,§ Tim Sparwasser,2,{ddagger} and Gottfried Alber1*

Institute of Immunology, College of Veterinary Medicine, University of Leipzig, An den Tierkliniken 11, 04103 Leipzig, Germany,1 Institute of Microbiology, Technische Universität München, Trogerstr. 30, 81675 Munich, Germany,2 Pfizer Animal Health, VMR&D, Biologicals Development, Ramsgate Road, IPC 188, Sandwich, Kent CT13 9NJ, United Kingdom,3 Max Planck Institute for Immunobiology, Stübeweg 51, 79108 Freiburg, Germany,4 Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, LGL, Oberschleissheim, Veterinärstrasse 2, 85164 Oberschleissheim, Germany,5 Gerhard-Domagk-Institute for Pathology, Universitätsklinikum Münster, Domagkstr.17, 48149 Münster, Germany6

Received 13 November 2008/ Accepted 17 June 2009

Parapoxvirus ovis (PPVO) is a member of the Poxviridae family and belongs to the genus Parapoxvirus. It displays only limited homology with orthopoxviruses and has some molecular features such as an unusual high GC content distinct from orthopoxviruses. Inactivated PPVO (iPPVO) displays strong immunostimulatory capacities mediating antiviral activity in vivo. The role of dendritic cells (DC) and the pattern recognition receptors and signaling requirements responsible for immunostimulation by iPPVO are unknown. We demonstrate here that bone marrow-derived plasmacytoid DC (BM-pDC) and bone marrow-derived conventional DC (BM-cDC) secrete alpha/beta interferon (IFN-{alpha}/β) in response to iPPVO. Furthermore, iPPVO induces tumor necrosis factor alpha (TNF-{alpha}) and interleukin-12/23p40 (IL-12/23p40) release and major histocompatibility complex class II (MHC-II), MHC-I, and CD86 upregulation by bone marrow-derived DC (BMDC). After engulfment, iPPVO is located in endosomal compartments and in the cytosol of BMDC. iPPVO elicits IFN-{alpha}/β by Toll-like receptor (TLR)-independent pathways in BM-cDC, since IFN-{alpha}/β release does not require myeloid differentiation primary response gene 88 (MyD88) or TIR-domain containing adaptor protein inducing interferon (TRIF). In contrast, iPPVO-induced TNF-{alpha} release and enhanced expression of MHC-I and CD86 but not of MHC-II by BMDC chiefly requires MyD88 but not TLR2 or TLR4. Induction of IFN-{alpha} by iPPVO in BM-cDC occurred in the absence of IFN regulatory factor 3 (IRF3) but required the presence of IRF7, whereas iPPVO-triggered IFN-β production required the presence of either IRF7 or IRF3. These results provide the first evidence that iPPVO mediates its immunostimulatory properties by TLR-independent and TLR-dependent pathways and demonstrate an important role of cDC for IFN-{alpha}/β production.

* Corresponding author. Mailing address: Institute of Immunology, College of Veterinary Medicine, University of Leipzig, An den Tierkliniken 11, 04103 Leipzig, Germany. Phone: 49-341-9738328. Fax: 49-341-9738147. E-mail: alber{at}rz.uni-leipzig.de

{triangledown} Published ahead of print on 1 July 2009.

# Present address: The Scripps Research Institute, Department of Immunology and Microbial Science, 10550 North Torrey Pines Rd., La Jolla, CA 92037.

{dagger} Present address: Helmholtz Centre for Environmental Research, Division of Health Research, Department of Proteomics, Permoserstr. 15, 04318 Leipzig, Germany.

§ Present address: Institute of Medical Microbiology, University Duisburg-Essen, Virchowstrasse 171, 45122 Essen, Germany.

{ddagger} Present address: Institute for Infection Immunology, Centre of Experimental and Clinical Infection Research, Twincore, Feodor-Lynen-Strasse 7, 30625 Hannover, Germany.

Journal of Virology, September 2009, p. 9411-9422, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.02362-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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