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

Z Waibler, M Anzaghe, H Ludwig, S Akira… - Journal of …, 2007 - Am Soc Microbiol
Z Waibler, M Anzaghe, H Ludwig, S Akira, S Weiss, G Sutter, U Kalinke
Journal of virology, 2007Am Soc Microbiol
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-
α) producers that were triggered independently of productive infection, viral replication, or …
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 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-α) producers that were triggered independently of productive infection, viral replication, or intermediate and late viral gene expression. Increased IFN-α 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-α 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-α responses that were only slightly reduced compared to those of wild-type mice. MVA-induced IFN-α responses were critically dependent on autocrine/paracrine triggering of the IFN-α/β receptor and were independent of IFN-β, 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.
American Society for Microbiology