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Abstract
Type 1 interferons induce the upregulation of hundreds of interferon-stimulated genes (ISGs) that combat viral replication. The parapoxvirus orf virus (ORFV) induces acute pustular skin lesions in sheep and goats and can reinfect its host, however, little is known of its ability to resist IFN. Vaccinia virus (VACV) encodes a number of factors that modulate the IFN response including the host-range genes C7L and K1L. A recombinant VACV-Western Reserve (WR) strain in which the K1L and C7L genes have been deleted does not replicate in cells treated with IFN-β nor in HeLa cells in which the IFN response is constitutive and is inhibited at the level of intermediate gene expression. Furthermore C7L is conserved in almost all poxviruses. We provide evidence that shows that although ORFV is more sensitive to IFN-β compared with VACV, and lacks homologues of KIL and C7L, it nevertheless has the ability to rescue a VACV KIL- C7L- gfp+ mutant in which gfp is expressed from a late promoter. Co-infection of HeLa cells with the mutant and ORFV demonstrated that ORFV was able to overcome the block in translation of intermediate transcripts in the mutant virus, allowing it to progress to late gene expression and new viral particles. Our findings strongly suggest that ORFV encodes a factor(s) that, although different in structure to C7L or KIL, targets an anti-viral cellular mechanism that is a highly potent at killing poxviruses.
Highlights
Type 1 IFNs are potent inhibitors of viral replication and are induced in most mammalian cells infected by viruses through Toll-like receptors, RIG-I/MDA5 RNA receptors and DNA sensors (Takaoka et al, 2007; Takeuchi and Akira, 2010; Jang et al, 2015)
Primary Lamb Testis (LT) cells were grown at 37◦C in minimal essential medium eagle (MEM) (Sigma) supplemented with 10% fetal calf serum (FCS) and 1% PSK antibiotic mix containing penicillin (500 units/ml), streptomycin (0.5 mg/ml) and kanamycin (0.1 mg/ml) (Robinson et al, 1982) Vero and HeLa cells were grown at 37◦C in Dulbecco’s Modified Eagle Medium (DMEM) (Sigma) supplemented with 10% fetal calf serum (FCS) and 1% PSK antibiotic mix. 143B cells that are thymidine kinase deficient (TK-), ATCC R CRL-8303TM and resistant to BUdR were grown at 37◦C in MEM supplemented with 10% FCS, 1% PSK antibiotic mix and 1% L-Glutamine
Our investigation focused on assays performed with primary Human Dermal Fibroblasts (HDF) and the ability of orf virus (ORFV) to replicate in cells in which the IFN response was induced
Summary
Type 1 IFNs are potent inhibitors of viral replication and are induced in most mammalian cells infected by viruses through Toll-like receptors, RIG-I/MDA5 RNA receptors and DNA sensors (Takaoka et al, 2007; Takeuchi and Akira, 2010; Jang et al, 2015). Type 1 IFNs induce an anti-viral state in neighboring cells via the janus kinase and signal activator of transcription (JAK/STAT) cell signaling pathway (Platanias, 2005; Sadler and Williams, 2008; Fensterl and Sen, 2009; Donnelly and Kotenko, 2010; MacMicking, 2012; Schneider et al, 2014) This leads to the upregulation of hundreds of interferon stimulated genes (ISGs) that inhibit viral replication (Schoggins and Rice, 2011; Schoggins et al, 2011; Schneider et al, 2014; Liu and Moss, 2018) at various stages of the virus life cycle including viral entry, replication, viral protein synthesis, and release (MacMicking, 2012; Schneider et al, 2014). IFITM proteins are enriched in late endosomes and lysosomes affecting viruses that require transit to these compartments for productive entry (Schoggins and Rice, 2011; MacMicking, 2012; Schneider et al, 2014)
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