Involvement of the cellular phosphatase DUSP1 in vaccinia virus infection

• Published in: PLoS pathogens 2013-11, Vol.9 (11), p.e1003719-e1003719
• Main Authors: Cáceres, Ana, Perdiguero, Beatriz, Gómez, Carmen E, Cepeda, Maria Victoria, Caelles, Carme, Sorzano, Carlos Oscar, Esteban, Mariano
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cercopithecus aethiops; Cèl·lules T; Dual Specificity Phosphatase 1 - genetics; Dual Specificity Phosphatase 1 - immunology; Dual Specificity Phosphatase 1 - metabolism; Experiments; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - immunology; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene expression; Health aspects; HeLa Cells; Host-parasite relationships; Humans; Immune response; Immune system; Immunity, Innate - genetics; Kinases; Malalties víriques; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - immunology; Morphogenesis; Phosphatases; Phosphorylation; Physiological aspects; Proteins; Resposta immunitària; T cells; Vaccinia; Vaccinia - enzymology; Vaccinia - genetics; Vaccinia - immunology; Vaccinia - pathology; Vaccinia virus - physiology; Viral proteins; Virus diseases; Virus Replication - physiology; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003719

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.