Abstract
Poxviruses encode a large variety of proteins that mimic, block or enhance host cell signaling pathways on their own benefit. It has been reported that mitogen-activated protein kinases (MAPKs) are specifically upregulated during vaccinia virus (VACV) infection. Here, we have evaluated the role of the MAPK negative regulator dual specificity phosphatase 1 (DUSP1) in the infection of VACV. We demonstrated that DUSP1 expression is enhanced upon infection with the replicative WR virus and with the attenuated VACV viruses MVA and NYVAC. This upregulation is dependent on early viral gene expression. In the absence of DUSP1 in cultured cells, there is an increased activation of its molecular targets JNK and ERK and an enhanced WR replication. Moreover, DUSP1 knock-out (KO) mice are more susceptible to WR infection as a result of enhanced virus replication in the lungs. Significantly, MVA, which is known to produce non-permissive infections in most mammalian cell lines, is able to grow in DUSP1 KO immortalized murine embryo fibroblasts (MEFs). By confocal and electron microscopy assays, we showed that in the absence of DUSP1 MVA morphogenesis is similar as in permissive cell lines and demonstrated that DUSP1 is involved at the stage of transition between IVN and MV in VACV morphogenesis. In addition, we have observed that the secretion of pro-inflammatory cytokines at early times post-infection in KO mice infected with MVA and NYVAC is increased and that the adaptive immune response is enhanced in comparison with WT-infected mice. Altogether, these findings reveal that DUSP1 is involved in the replication and host range of VACV and in the regulation of host immune responses through the modulation of MAPKs. Thus, in this study we demonstrate that DUSP1 is actively involved in the antiviral host defense mechanism against a poxvirus infection.
Highlights
Poxviruses have evolved to efficiently counteract host immune responses through the modulation of extracellular and intracellular environment of the infected cell
We have showed that dual specificity phosphatase 1 (DUSP1) expression is upregulated during vaccinia virus (VACV) infection and that DUSP1 plays an important role in VACV replication
We showed that replication of Western Reserve (WR) and Modified Vaccinia virus Ankara (MVA) is enhanced in the absence of DUSP1 and that, interestingly, DUSP1 is a key factor during MVA morphogenesis in murine cells
Summary
Poxviruses have evolved to efficiently counteract host immune responses through the modulation of extracellular and intracellular environment of the infected cell. VACV encodes its own kinases and phosphatases [14], [15], [16] but it is able to benefit from the activity of cellular proteins such as the ones belonging to the family of MAPKs which consists of p38MAPK, ERK and JNK. As MAPKs are activated by phosphorylation by upstream MAPKKs [22], the cell encodes phosphatases that bind to MAPKs and inactivate them by removing the phosphates on the Thr-Xaa-Tyr motif. Among these phosphatases, DUSPs provide an important negative feedback mechanism for MAPK activation [23]. The family of DUSPs shares a common kinase interaction motif (KIM) located at the N-terminal region and a catalytic domain at the C-terminal region
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