Vaccinia virus serpin B13R (SPI-2) inhibits interleukin-1beta-converting enzyme and protects virus-infected cells from TNF- and Fas-mediated apoptosis, but does not prevent IL-1beta-induced fever.
The vaccinia virus (VV) strain Western Reserve B13R gene encodes a 38.5 kDa intracellular polypeptide that is non-essential for virus replication in vitro and does not affect virus virulence in a murine intranasal model. The protein has 92% amino acid identity with the cowpox virus cytokine response modifier A (crmA) protein which inhibits the interleukin (IL)-1beta converting enzyme (ICE). Here, we show that extracts from THP-1 cells infected with VV strains expressing B13R prevent the cleavage of in vitro transcribed and translated pro-IL-1beta into mature IL-1beta. Similarly, THP-1 cells infected with VVs expressing B13R process pro-IL-1beta into mature IL-1beta inefficiently in situ. Despite its inhibition of ICE, B13R does not prevent fever in infected mice, a systemic effect mediated by IL-1beta. Instead, fever is controlled by the VV IL-1beta receptor, encoded by gene B15R, and deletion of both the B13R and B15R genes did not increase the febrile response compared to deletion of B15R alone. The B13R protein does, however, block apoptosis mediated by anti-Fas antibodies or by tumour necrosis factor (TNF) and cycloheximide. Using DNA fragmentation, chromium release and microscopic analyses it was shown that cells infected with wild-type VV strain WR, or a revertant virus in which the B13R gene had been re-inserted into the B13R deletion mutant, are more resistant than uninfected cells or deletion mutant-infected cells to apoptosis mediated by anti-Fas and TNF.
Kettle
S
S
Sir William Dunn School of Pathology, University of Oxford, UK.
Alcamí
A
A
Khanna
A
A
Ehret
R
R
Jassoy
C
C
Smith
G L
GL
D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005334:Fever / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015843:Serpins / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D014774:Virulence; D019014:fas Receptor / Q000378:metabolism*
D000956:Antigens, Viral; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D003546:Cysteine Endopeptidases; D020170:Caspase 1