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A bioassay that measured the interleukin (IL)-12-induced production of interferon (IFN)-gamma from mouse splenocytes was used to identify a soluble factor in the supernatants of vaccinia virus (VV)-infected cells that inhibited the production of IFN-gamma. This soluble factor was expressed by 14 out of 16 VV strains including the Western Reserve (WR) strain, but strains Copenhagen and Tashkent and a mutant of strain WR called 6/2 lacked this activity. The gene encoding this activity was identified as C12L by transferring DNA present in VV WR but missing in VV WR 6/2 into VV Copenhagen and testing for expression of the soluble factor. The C12L protein shows amino acid similarity to IL-18 binding proteins that are encoded by poxviruses, mice and humans, and C12L protein produced from VV or baculovirus inhibited the biological activity of mouse IL-18 in vitro. Thus the inhibition of IL-12-induced IFN-gamma production was due to indirect effects of C12L on IL-18, illustrating the synergistic action of these pro-inflammatory cytokines. To study the role of the C12L protein in the virus life-cycle, we constructed a deletion mutant lacking the C12L gene and a revertant virus in which the gene was reinserted into the deletion mutant. In vitro the replication and plaque size of these viruses were indistinguishable. However, infection of BALB/c mice by the intranasal route showed that the deletion mutant was attenuated and induced lower weight loss and signs of illness compared to controls.

Original publication

DOI

10.1099/0022-1317-83-11-2833

Type

Journal article

Journal

J Gen Virol

Publication Date

11/2002

Volume

83

Pages

2833 - 2844

Keywords

Administration, Intranasal, Animals, Base Sequence, Cell Line, Cells, Cultured, Cercopithecus aethiops, Chromosome Mapping, DNA, Viral, Disease Models, Animal, Gene Expression, Humans, Interferon-gamma, Interleukin-12, Interleukin-18, Mice, Mice, Inbred BALB C, Mice, Inbred CBA, Molecular Sequence Data, Poxviridae, Spleen, Time Factors, Vaccinia, Vaccinia virus, Viral Proteins, Virulence, Virus Replication