Discrimination of Mumps Virus Small Hydrophobic Gene Deletion Effects from Gene Translation Effects on Virus Virulence

Malik, Tahir; Shegogue, Candie Wolbert; Werner, Kellie; Ngo, Laurie; Sauder, Christian; Zhang, Cheryl; Duprex, W. Paul; Rubin, Steven A.

doi:10.1128/jvi.02686-10

Cited by 20 publications

(14 citation statements)

References 26 publications

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“…We did not observe MuV SH to have a severe impact on virus replication in cell culture, which is in line with previous findings by Malik et al (33). In a neurotoxicity test involving intracerebral injection of MuV into the brain of newborn rats (54), rMuV lacking the entire SH gene was shown to be attenuated, while rMuV deficient in SH due to additional stop codons was not (33). However, effects on NF-B signaling might become evident only in a more physiological setting, i.e., during MuV infection via the respiratory tract.…”

Section: Discussionsupporting

confidence: 93%

“…Efficient paramyxovirus replication is dependent on a well-balanced gradient of viral mRNAs, provided by the order and the number of viral genes on the single-stranded RNA genome (31), as well as on a hexameric genome length (rule of six) for promoter recognition and viral editing (32). In order to generate rMuV deficient in SH with the least possible effect on virus replication, we introduced three stop codons into the SH gene (similar to Malik et al [33]). To allow the detection of SH in infected cells, we additionally fused a FLAG epitope coding sequence to the SH gene while complying with the rule of six.…”

Section: Discussionmentioning

confidence: 99%

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Mumps Virus SH Protein Inhibits NF-κB Activation by Interacting with Tumor Necrosis Factor Receptor 1, Interleukin-1 Receptor 1, and Toll-Like Receptor 3 Complexes

Franz

Rennert

Woznik

et al. 2017

J Virol

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The mumps virus (MuV) small hydrophobic protein (SH) is a type I membrane protein expressed in infected cells. SH has been reported to interfere with innate immunity by inhibiting tumor necrosis factor alpha (TNF-␣)-mediated apoptosis and NF-B activation. To elucidate the underlying mechanism, we generated recombinant MuVs (rMuVs) expressing the SH protein with an N-terminal FLAG epitope or lacking SH expression due to the insertion of three stop codons into the SH gene. Using these viruses, we were able to show that SH reduces the phosphorylation of IKK␤, IB␣, and p65 as well as the translocation of p65 into the nucleus of infected A549 cells. Reporter gene assays revealed that SH interferes not only with TNF-␣-mediated NF-B activation but also with IL-1␤-and poly(I·C)-mediated NF-B activation, and that this inhibition occurs upstream of the NF-B pathway components TRAF2, TRAF6, and TAK1. Since SH coimmunoprecipitated with tumor necrosis factor receptor 1 (TNFR1), RIP1, and IRAK1, we hypothesize that SH exerts its inhibitory function by interacting with TNFR1, interleukin-1 receptor type 1 (IL-1R1), and TLR3 complexes in the plasma membrane of infected cells.IMPORTANCE The MuV SH has been shown to impede TNF-␣-mediated NF-B activation and is therefore thought to contribute to viral immune evasion. However, the mechanisms by which SH mediates NF-B inhibition remained largely unknown. In this study, we show that SH interacts with TNFR1, IL-1R1, and TLR3 complexes in infected cells. We thereby not only shed light on the mechanisms of SH-mediated NF-B inhibition but also reveal that SH interferes with NF-B activation induced by interleukin-1␤ (IL-1␤) and double-stranded RNA.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Mumps Virus SH Protein Inhibits NF-κB Activation by Interacting with Tumor Necrosis Factor Receptor 1, Interleukin-1 Receptor 1, and Toll-Like Receptor 3 Complexes

Franz

Rennert

Woznik

et al. 2017

J Virol

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show abstract

“…The related MuV SH protein is a 57-residue integral membrane protein, which due to sequence variability has been used as marker to identify MuV isolates [27]. MuV lacking an SH gene induced levels of cytokine responses higher than WT and was attenuated in an animal model system [28], although the effect of the SH gene deletion on the gradient of viral gene transcription also likely contributes to these results [29]. …”

Section: Expression Of Paramyxovirus Antagonists Of Innate Immunitymentioning

confidence: 99%

Paramyxovirus Activation and Inhibition of Innate Immune Responses

Parks

Alexander-Miller

2013

Journal of Molecular Biology

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Paramyxoviruses represent a remarkably diverse family of enveloped nonsegmented negative-strand RNA viruses, some of which are the most ubiquitous disease-causing viruses of humans and animals. This review focuses on paramyxovirus activation of innate immune pathways, the mechanisms by which these RNA viruses counteract these pathways, and the innate response to paramyxovirus infection of dendritic cells (DC). Paramyxoviruses are potent activators of extracellular complement pathways, a first line of defense that viruses must face during natural infections. We discuss mechanisms by which these viruses activate and combat complement to delay neutralization. Once cells are infected, virus replication drives type I interferon (IFN) synthesis that has the potential to induce a large number of antiviral genes. Here we describe four approaches by which paramyxoviruses limit IFN induction: by limiting synthesis of IFN-inducing aberrant viral RNAs, through targeted inhibition of RNA sensors, by providing viral decoy substrates for cellular kinase complexes, and through direct blocking of the IFN promoter. In addition, paramyxoviruses have evolved diverse mechanisms to disrupt IFN signaling pathways. We describe three general mechanisms, including targeted proteolysis of signaling factors, sequestering cellular factors, and upregulation of cellular inhibitors. DC are exceptional cells with the capacity to generate adaptive immunity through the coupling of innate immune signals and T cell activation. We discuss the importance of innate responses in DC following paramyxovirus infection and their consequences for the ability to mount and maintain antiviral T cells.

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“…The functions of V and SH are less well understood [2][3][4][5]. The SH gene sequence is variable and is therefore used as the basis of MuV genotyping [6][7][8].…”

Section: Open Accessmentioning

confidence: 99%

Comparison of the live attenuated mumps vaccine (Miyahara strain) with its preattenuated parental strain

Nagata¹,

Maedera²,

Nagata³

et al. 2013

J Vaccines Immun

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Discrimination of Mumps Virus Small Hydrophobic Gene Deletion Effects from Gene Translation Effects on Virus Virulence

Cited by 20 publications

References 26 publications

Mumps Virus SH Protein Inhibits NF-κB Activation by Interacting with Tumor Necrosis Factor Receptor 1, Interleukin-1 Receptor 1, and Toll-Like Receptor 3 Complexes

Mumps Virus SH Protein Inhibits NF-κB Activation by Interacting with Tumor Necrosis Factor Receptor 1, Interleukin-1 Receptor 1, and Toll-Like Receptor 3 Complexes

Paramyxovirus Activation and Inhibition of Innate Immune Responses

Comparison of the live attenuated mumps vaccine (Miyahara strain) with its preattenuated parental strain

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