Morbillivirus V Proteins Exhibit Multiple Mechanisms to Block Type 1 and Type 2 Interferon Signalling Pathways

Chinnakannan, Senthil; Nanda, Sambit K.; Baron, Michael D.

doi:10.1371/journal.pone.0057063

Cited by 64 publications

(90 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although there are no antibodies available that recognise the PPRV V or C proteins, we confirmed the expression of V protein by rNigeria/75/1_ΔC and its absence in rNigeria/75/1_ΔV by using the known ability of PPRV V protein to block IFN-α-stimulated phosphorylation of STAT1 in infected cells [59]. We infected VHS cells with the parental virus or with one of the two mutants, and left the infection for 18 or 40 hours before treating the cells with IFN-α and labelling intracellular phosphorylated STAT1 (STAT1P) for immunofluorescence (Fig 8).…”

Section: Resultsmentioning

confidence: 62%

“…The expression plasmids for the V and C proteins of RPV/Saudi/81 (pcDNA-RPV-V-V5 [58] and pcDNA-RPV-C-V5 [91]) and the V protein of the wild type PPRV/Turkey/2000 isolate (pcDNA-PPRV-V-V5 [59]) have also been described. The corresponding expression construct for the PPRV/Turkey/2000 C protein (pcDNA-PPRV-C-V5) was made by amplifying the C protein ORF from a clone of the P gene and inserting it into pcDNA6/V5/His.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Control of the induction of type I interferon by Peste des petits ruminants virus

2017

Self Cite

View full text Add to dashboard Cite

Peste des petits ruminants virus (PPRV) is a morbillivirus that produces clinical disease in goats and sheep. We have studied the induction of interferon-β (IFN-β) following infection of cultured cells with wild-type and vaccine strains of PPRV, and the effects of such infection with PPRV on the induction of IFN-β through both MDA-5 and RIG-I mediated pathways. Using both reporter assays and direct measurement of IFN-β mRNA, we have found that PPRV infection induces IFN-β only weakly and transiently, and the virus can actively block the induction of IFN-β. We have also generated mutant PPRV that lack expression of either of the viral accessory proteins (V&C) to characterize the role of these proteins in IFN-β induction during virus infection. Both PPRV_ΔV and PPRV_ΔC were defective in growth in cell culture, although in different ways. While the PPRV V protein bound to MDA-5 and, to a lesser extent, RIG-I, and over-expression of the V protein inhibited both IFN-β induction pathways, PPRV lacking V protein expression can still block IFN-β induction. In contrast, PPRV C bound to neither MDA-5 nor RIG-I, but PPRV lacking C protein expression lost the ability to block both MDA-5 and RIG-I mediated activation of IFN-β. These results shed new light on the inhibition of the induction of IFN-β by PPRV.

show abstract

Section: Resultsmentioning

confidence: 62%

Section: Methodsmentioning

confidence: 99%

Control of the induction of type I interferon by Peste des petits ruminants virus

2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Morbilliviruses interfere with IFN activation by preventing the nuclear translocation of STAT1 and STAT2 (28) as well as downstream signaling through the intracellular pattern recognition receptor mda5 (7,29). The V-protein residues involved in these functions have been mapped for MeV (8,19), and the importance of Y110H for STAT1 binding and the region for STAT2 and mda5 interactions has been demonstrated for other morbilliviruses (16,30). To investigate the roles of the different signaling pathways in morbillivirus pathogenesis, we selectively generated STAT1-, STAT2-, or mda5-blind CDV V proteins and a V protein with a disrupted zinc-binding domain (ZBDko) in the genetic background of the wild-type strain 5804P.…”

Section: Resultsmentioning

confidence: 99%

“…It is now clear that V protein inhibits the nuclear translocation of STAT1 and STAT2, thereby interfering with type I and II IFN-mediated transcriptional activation (16,28,30). In addition, V protein inhibits mda5 signaling (19).…”

Section: Discussionmentioning

confidence: 99%

Morbillivirus Control of the Interferon Response: Relevance of STAT2 and mda5 but Not STAT1 for Canine Distemper Virus Virulence in Ferrets

Svitek

Gerhauser

Gonçalves

et al. 2014

J Virol

View full text Add to dashboard Cite

The V proteins of paramyxoviruses control the innate immune response. In particular, the V protein of the genus Morbillivirus interferes with the signal transducer and activator of transcription 1 (STAT1), STAT2, and melanoma differentiation-associated protein 5 (mda5) signaling pathways. To characterize the contributions of these pathways to canine distemper virus (CDV) pathogenesis, we took advantage of the knowledge about the mechanisms of interaction between the measles virus V protein with these key regulators of innate immunity. We generated recombinant CDVs with V proteins unable to properly interact with STAT1, STAT2, or mda5. A virus with combined STAT2 and mda5 deficiencies was also generated, and available wild-type and V-protein-knockout viruses were used as controls. Ferrets infected with wild-type and STAT1-blind viruses developed severe leukopenia and loss of lymphocyte proliferation activity and succumbed to the disease within 14 days. In contrast, animals infected with viruses with STAT2 or mda5 defect or both STAT2 and mda5 defects developed a mild self-limiting disease similar to that associated with the V-knockout virus. This study demonstrates the importance of interference with STAT2 and mda5 signaling for CDV immune evasion and provides a starting point for the development of morbillivirus vectors with reduced immunosuppressive properties. IMPORTANCEThe V proteins of paramyxoviruses interfere with the recognition of the virus by the immune system of the host. For morbilliviruses, the V protein is known to interact with the signal transducer and activator of transcription 1 (STAT1) and STAT2 and the melanoma differentiation-associated protein 5 (mda5), which are involved in interferon signaling. Here, we examined the contribution of each of these signaling pathways to the pathogenesis of the carnivore morbillivirus canine distemper virus. Using viruses selectively unable to interfere with the respective signaling pathway to infect ferrets, we found that inhibition of STAT2 and mda5 signaling was critical for lethal disease. Our findings provide new insights in the mechanisms of morbillivirus immune evasion and may lead to the development of new vaccines and oncolytic vectors. M orbilliviruses, including measles virus (MeV), which infects humans and certain nonhuman primates, and the carnivore morbillivirus canine distemper virus (CDV), cause a severe acute disease characterized by rash, fever, and respiratory and gastrointestinal symptoms, followed by generalized immunosuppression (1-3). This rapid and profound immunosuppression facilitates secondary infections, which make important contributions to morbillivirus-associated morbidity and mortality (4, 5). The morbillivirus V protein is the primary viral immune interference protein, targeting the innate host response at multiple levels (6-8). The V-protein mRNA is transcribed from the phosphoprotein (P) gene by insertion of a nontemplated guanosine at an editing site located in the middle of the gene (9, 10). Consequently, V shares i...

show abstract

“…Stable cell generation employed the pdlNotInPkMCSR expression construct (38) with cloning into the MluI and SpeI sites. Lentivirus was…”

mentioning

confidence: 99%

Molluscum Contagiosum Virus Protein MC005 Inhibits NF-κB Activation by Targeting NEMO-Regulated IκB Kinase Activation

Brady

Haas

Farrell

et al. 2017

J Virol

View full text Add to dashboard Cite

Molluscum contagiosum virus (MCV), the only known extant humanadapted poxvirus, causes a long-duration infection characterized by skin lesions that typically display an absence of inflammation despite containing high titers of live virus. Despite this curious presentation, MCV is very poorly characterized in terms of host-pathogen interactions. The absence of inflammation around MCV lesions suggests the presence of potent inhibitors of human antiviral immunity and inflammation. However, only a small number of MCV immunomodulatory genes have been characterized in detail. It is likely that many more remain to be discovered, given the density of such sequences in other poxvirus genomes. NF-B activation occurs in response to both virus-induced pattern recognition receptor (PRR) signaling and cellular activation by virus-induced proinflammatory cytokines like tumor necrosis factor and interleukin-1. Activated NF-B drives cytokine and interferon gene expression, leading to inflammation and virus clearance. We report that MC005, which has no orthologs in other poxvirus genomes, is a novel inhibitor of PRR-and cytokinestimulated NF-B activation. MC005 inhibited NF-B proximal to the IB kinase (IKK) complex, and unbiased affinity purification revealed that MC005 interacts with the IKK subunit NEMO (NF-B essential modulator). MC005 binding to NEMO prevents the conformational priming of the IKK complex that occurs when NEMO binds to ubiquitin chains during pathway activation. These data reveal a novel mechanism of poxvirus inhibition of human innate immunity, validate current dynamic models of NEMO-dependent IKK complex activation, and further clarify how the humanadapted poxvirus MCV can so effectively evade antiviral immunity and suppress inflammation to persist in human skin lesions.IMPORTANCE Poxviruses adapt to specific hosts over time, evolving and tailoring elegantly precise inhibitors of the rate-limiting steps within the signaling pathways that control innate immunity and inflammation. These inhibitors reveal new features of the antiviral response, clarify existing models of signaling regulation while offering potent new tools for approaching therapeutic intervention in autoimmunity and inflammatory disease. Molluscum contagiosum virus (MCV) is the only known extant poxvirus specifically adapted to human infection and appears adept at evading normal human antiviral responses, yet it remains poorly characterized. We report the identification of MCV protein MC005 as an inhibitor of the pathways leading to the activation of NF-B, an essential regulator of innate immunity. Further, identification of the mechanism of inhibition of NF-B by MC005 confirms current models of the complex way in which NF-B is regulated and greatly expands our understanding of how MCV so effectively evades human immunity.

show abstract

Morbillivirus V Proteins Exhibit Multiple Mechanisms to Block Type 1 and Type 2 Interferon Signalling Pathways

Cited by 64 publications

References 65 publications

Control of the induction of type I interferon by Peste des petits ruminants virus

Control of the induction of type I interferon by Peste des petits ruminants virus

Morbillivirus Control of the Interferon Response: Relevance of STAT2 and mda5 but Not STAT1 for Canine Distemper Virus Virulence in Ferrets

Molluscum Contagiosum Virus Protein MC005 Inhibits NF-κB Activation by Targeting NEMO-Regulated IκB Kinase Activation

Contact Info

Product

Resources

About