Vaccinia virus-mediated inhibition of type I interferon responses is a multifactorial process involving the soluble type I interferon receptor B18 and intracellular components.
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-alpha, whereas the latter variant did induce IFN-beta. 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-alpha but not IFN-beta. In the same direction, a B18R-deficient VACV variant triggered only IFN-alpha, confirming B18 as the soluble IFN-alpha 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-alpha and IFN-beta responses.
Waibler
Zoe
Z
Paul-Ehrlich-Institut, Langen, Germany.
Anzaghe
Martina
M
Frenz
Theresa
T
Schwantes
Astrid
A
Pöhlmann
Christopher
C
Ludwig
Holger
H
Palomo-Otero
Marcos
M
Alcamí
Antonio
A
Sutter
Gerd
G
Kalinke
Ulrich
U
D000818:Animals; D002478:Cells, Cultured; D054884:Host-Pathogen Interactions; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000378:metabolism*; D014616:Vaccinia virus / Q000276:immunology*; D014764:Viral Proteins / Q000378:metabolism*
D007370:Interferon Type I; D011506:Proteins; D014764:Viral Proteins; C067853:B18R protein, Vaccinia virus