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J. Virol. doi:10.1128/JVI.01190-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Modified vaccinia virus Ankara induces Toll-like receptor independent type I interferon responses

Division of Immunology, Paul-Ehrlich-Institut, D-63225 Langen, Germany; Division of Virology, Paul-Ehrlich-Institut, D-63225 Langen, Germany; Department of Host Defense, Research Institute of Microbial Diseases, Osaka University, Suita-ku, Osaka 565-0871, Japan; Molekulare Immunologie, Helmholtz Zentrum für Infektionsforschung, D-38124 Braunschweig, Germany

^* To whom correspondence should be addressed. Email: kalul{at}pei.de.

	Abstract

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 DNA encoded MVA induces type I interferon (IFN) responses. MVA stimulation of bone marrow derived dendritic cells (DC) showed that plasmacytoid DC were main 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 virus encoded immune-modulator(s) interfered with the host cytokine response. Mice devoid of Toll-like receptor (TLR) 9, the receptor for double stranded DNA, mounted normal IFN- responses upon MVA treatment. Furthermore, mice devoid of adaptors of TLR signaling, MyD88 or TRIF, and mice deficient of protein kinase R (PKR) showed IFN- responses that were only slightly reduced when compared to wild-type mice. MVA induced IFN- responses were critically dependent on autocrine/paracrine triggering of the IFN-/ receptor (IFNAR) and were independent of IFN-, thus involving "half" 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.