Modified vaccinia virus Ankara induces Toll-like receptor-independent type I interferon responses.
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-alpha) producers that were triggered independently of productive infection, viral replication, or intermediate and late viral gene expression. Increased IFN-alpha 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-alpha 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-alpha responses that were only slightly reduced compared to those of wild-type mice. MVA-induced IFN-alpha responses were critically dependent on autocrine/paracrine triggering of the IFN-alpha/beta receptor and were independent of IFN-beta, 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.
Waibler
Zoe
Z
Division of Immunology, Paul-Ehrlich-Institut, D-63225, Langen, Germany.
Anzaghe
Martina
M
Ludwig
Holger
H
Akira
Shizuo
S
Weiss
Siegfried
S
Sutter
Gerd
G
Kalinke
Ulrich
U
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D015870:Gene Expression; D007370:Interferon Type I / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D012900:Smallpox Vaccine / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D014779:Virus Replication
D033942:Adaptor Proteins, Vesicular Transport; D019496:Cancer Vaccines; D007370:Interferon Type I; D016898:Interferon-alpha; D016899:Interferon-beta; D053594:Myeloid Differentiation Factor 88; D012900:Smallpox Vaccine; D051217:Toll-Like Receptor 9; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse