This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Waibler, Z. Articles by Kalinke, U. Search for Related Content PubMed PubMed Citation Articles by Waibler, Z. Articles by Kalinke, U.

 Previous Article  |  Next Article 

Journal of Virology, February 2009, p. 1563-1571, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01617-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Vaccinia Virus-Mediated Inhibition of Type I Interferon Responses Is a Multifactorial Process Involving the Soluble Type I Interferon Receptor B18 and Intracellular Components

Zoe Waibler,^1,# Martina Anzaghe,^1,# Theresa Frenz,¹ Astrid Schwantes,² Christopher Pöhlmann,² Holger Ludwig,² Marcos Palomo-Otero,³ Antonio Alcamí,³ Gerd Sutter,² and Ulrich Kalinke^1*

Division of Immunology, Paul-Ehrlich-Institut, D-63225 Langen, Germany,¹ Division of Virology, Paul-Ehrlich-Institut, D-63225 Langen, Germany,² Centro de Biología Molecular Severo Ochoa Universidad Autonoma de Madrid and Consejo Superior de Investigaciones Cientificas Cantoblanco, 28049 Madrid, Spain³

Received 29 July 2008/ Accepted 2 December 2008

Poxviruses such as virulent vaccinia virus (VACV) strain Western Reserve encode a broad range of immune modulators that interfere with host responses to infection. Upon more than 570 in vitro passages in chicken embryo fibroblasts (CEF), chorioallantois VACV Ankara (CVA) accumulated mutations that resulted in highly attenuated modified vaccinia virus Ankara (MVA). MVA infection of mice and of dendritic cells (DC) induced significant type I interferon (IFN) responses, whereas infection with VACV alone or in combination with MVA did not. These results implied that VACV expressed an IFN inhibitor(s) that was functionally deleted in MVA. To further characterize the IFN inhibitor(s), infection experiments were carried out with CVA strains isolated after 152 (CVA152) and 386 CEF passages (CVA386). Interestingly, neither CVA152 nor CVA386 induced IFN-, whereas the latter variant did induce IFN-β. This pattern suggested a consecutive loss of inhibitors during MVA attenuation. Similar to supernatants of VACV- and CVA152-infected DC cultures, recombinantly expressed soluble IFN decoy receptor B18, which is encoded in the VACV genome, inhibited MVA-induced IFN- but not IFN-β. In the same direction, a B18R-deficient VACV variant triggered only IFN-, confirming B18 as the soluble IFN- inhibitor. Interestingly, VACV infection inhibited IFN responses induced by a multitude of different stimuli, including oligodeoxynucleotides containing CpG motifs, poly(I:C), and vesicular stomatitis virus. Collectively, the data presented show that VACV-mediated IFN inhibition is a multistep process involving secreted factors such as B18 plus intracellular components that cooperate to efficiently shut off systemic IFN- and IFN-β responses.

---

* Corresponding author. Present address: TWINCORE, Centre for Experimental and Clinical Infection Research, founded by the Hannover Medical School and the Helmholtz Centre for Infection Research, D-30625 Hannover, Germany. Phone: 49-511-220027100. Fax: 49-511-220027-186. E-mail: ulrich.kalinke{at}twincore.de

Published ahead of print on 10 December 2008.

^# Both authors contributed equally to this work.

---

Journal of Virology, February 2009, p. 1563-1571, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01617-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.