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Modified Vaccinia Virus Ankara Induces Toll-Like Receptor-Independent Type I Interferon Responses

Zoe Waibler,^1, Martina Anzaghe,^1, Holger Ludwig,² Shizuo Akira,³ Siegfried Weiss,⁴ 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 Department of Host Defense, Research Institute of Microbial Diseases, Osaka University, Suita-ku, Osaka 565-0871, Japan,³ Molekulare Immunologie, Helmholtz Zentrum für Infektionsforschung, D-38124 Braunschweig, Germany⁴

Received 31 May 2007/ Accepted 30 August 2007

Modified vaccinia virus Ankara (MVA) is a highly attenuated vaccinia virus strain undergoing clinical evaluation as a replication-deficient vaccine vector against various infections and tumor diseases. To analyze the basis of its high immunogenicity, we investigated the mechanism of how MVA induces type I interferon (IFN) responses. MVA stimulation of bone marrow-derived dendritic cells (DC) showed that plasmacytoid DC were main alpha IFN (IFN-) producers that were triggered independently of productive infection, viral replication, or intermediate and late viral gene expression. Increased IFN- levels were induced upon treatment with mildly UV-irradiated MVA, suggesting that a virus-encoded immune modulator(s) interfered with the host cytokine response. Mice devoid of Toll-like receptor 9 (TLR9), the receptor for double-stranded DNA, mounted normal IFN- responses upon MVA treatment. Furthermore, mice devoid of the adaptors of TLR signaling MyD88 and TRIF and mice deficient in protein kinase R (PKR) showed IFN- responses that were only slightly reduced compared to those of wild-type mice. MVA-induced IFN- responses were critically dependent on autocrine/paracrine triggering of the IFN-/ß receptor and were independent of IFN-ß, thus involving "one-half" of a positive-feedback loop. In conclusion, MVA-mediated type I IFN secretion was primarily triggered by non-TLR molecules, was independent of virus propagation, and critically involved IFN feedback stimulation. These data provide the basis to further improve MVA as a vaccine vector.

Published ahead of print on 12 September 2007.

Both authors contributed equally to this work.