Abstract
The avian pathogen fowlpox virus (FWPV) has been successfully used as a vaccine vector in poultry and humans, but relatively little is known about its ability to modulate host antiviral immune responses in these hosts, which are replication-permissive and nonpermissive, respectively. FWPV is highly resistant to avian type I interferon (IFN) and able to completely block the host IFN-response. Microarray screening of host IFN-regulated gene expression in cells infected with 59 different, nonessential FWPV gene knockout mutants revealed that FPV184 confers immunomodulatory capacity. We report that the FPV184-knockout virus (FWPVΔ184) induces the cellular IFN response as early as 2 h postinfection. The wild-type, uninduced phenotype can be rescued by transient expression of FPV184 in FWPVΔ184-infected cells. Ectopic expression of FPV184 inhibited polyI:C activation of the chicken IFN-β promoter and IFN-α activation of the chicken Mx1 promoter. Confocal and correlative super-resolution light and electron microscopy demonstrated that FPV184 has a functional nuclear localisation signal domain and is packaged in the lateral bodies of the virions. Taken together, these results provide a paradigm for a late poxvirus structural protein packaged in the lateral bodies, capable of suppressing IFN induction early during the next round of infection.
Highlights
Poxviruses are large, enveloped, double-stranded DNA viruses capable of causing disease in mammals, birds and insects
We use our existing FP9 knockout library [20] to screen infected primary chicken embryo fibroblasts (CEFs) for fowlpox virus (FWPV) genes that modulate the induction of interferon-regulated genes (IRG)s
Consistent with its ability to modulate IFN-stimulated genes (ISGs) responses soon after infection and long before de novo production, we show that FPV184 is packaged into FWPV particles where it resides in lateral bodies (LBs)
Summary
Poxviruses are large, enveloped, double-stranded DNA viruses capable of causing disease in mammals, birds and insects. Some of the first viral anti-IFN defence mechanisms were elucidated using vaccinia virus (VACV), which expresses multiple, often redundant inhibitors of IFN induction, JAK/STAT signalling and IFN-stimulated genes (ISGs), as well as IFN-receptor antagonists and mimics of IFN ligands [7,8,9,10,11,12]. We use our existing FP9 knockout library [20] to screen infected primary chicken embryo fibroblasts (CEFs) for FWPV genes that modulate the induction of interferon-regulated genes (IRG)s. Using this approach, we identified FPV184 as a third FWPV immunomodulatory protein blocking the induction of innate immune responses. These results suggest that the packaging of late immunomodulatory proteins and their subsequent delivery into the nucleus of newly infected cells serve as an immediate–early innate immune evasion strategy
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