Abstract
Myxoma virus (MYXV) is a Leporipoxvirus that possesses a specific rabbit-restricted host tropism but exhibits a much broader cellular host range in cultured cells. MYXV is able to efficiently block all aspects of the type I interferon (IFN)-induced antiviral state in rabbit cells, partially in human cells and very poorly in mouse cells. The mechanism(s) of this species-specific inhibition of type I IFN-induced antiviral state is not well understood. Here we demonstrate that MYXV encoded protein M029, a truncated relative of the vaccinia virus (VACV) E3 double-stranded RNA (dsRNA) binding protein that inhibits protein kinase R (PKR), can also antagonize the type I IFN-induced antiviral state in a highly species-specific manner. In cells pre-treated with type I IFN prior to infection, MYXV exploits M029 to overcome the induced antiviral state completely in rabbit cells, partially in human cells, but not at all in mouse cells. However, in cells pre-infected with MYXV, IFN-induced signaling is fully inhibited even in the absence of M029 in cells from all three species, suggesting that other MYXV protein(s) apart from M029 block IFN signaling in a species-independent manner. We also show that the antiviral state induced in rabbit, human or mouse cells by type I IFN can inhibit M029-knockout MYXV even when PKR is genetically knocked-out, suggesting that M029 targets other host proteins for this antiviral state inhibition. Thus, the MYXV dsRNA binding protein M029 not only antagonizes PKR from multiple species but also blocks the type I IFN antiviral state independently of PKR in a highly species-specific fashion.
Highlights
Evasion of host innate immune responses is one of the key steps for successful replication and pathogenesis for all viruses that infect vertebrate hosts
Myxoma virus (MYXV) sensitivity to type I IFN-induced antiviral state in human and mouse cells cannot be rescued even in the absence of protein kinase R (PKR). These results demonstrate that the MYXV double-stranded RNA (dsRNA) binding protein M029 blocks IFN-induced antiviral pathways and mediates species-specific permissiveness in cells, but via both PKR-dependent and –independent pathways
In RK13 cells, treatment with any of these type I IFNs completely blocked the replication of control vesicular stomatitis virus (VSV) virus, suggesting that antiviral states induced by these type I IFNs are functional (Figure 1A)
Summary
Evasion of host innate immune responses is one of the key steps for successful replication and pathogenesis for all viruses that infect vertebrate hosts. Type I interferons (IFNs) play a central role in inducing early antiviral responses to combat most virus infections [1,2]. IFN ligands is initiated upon innate sensing of viruses and their virus-induced pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs). Activation of PRRs induces signaling cascades that lead to the rapid expression of genes encoding antiviral cytokines, such as the type I IFNs. Induced IFNs are secreted and bind their cognate receptors on either the same virus-infected cells (autocrine stimulation) or on neighboring uninfected cells (paracrine stimulation) to initiate the IFN signaling cascade that leads to the formation of a transcriptional activation complex called ISGF3, which upregulates a large suite of IFN-stimulated genes (ISGs).
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