BST2/Tetherin Overexpression Modulates Morbillivirus Glycoprotein Production to Inhibit Cell–Cell Fusion

Kelly, James; Human, Stacey; Alderman, Joseph; Jobe, Fatoumatta; Logan, Leanne; Rix, Thomas Andersen; Gonçalves-Carneiro, Daniel; Leung, Corwin; Thakur, Nazia; Birch, Jamie; Bailey, Dalan

doi:10.3390/v11080692

Cited by 10 publications

(11 citation statements)

References 40 publications

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“…The antiviral response is mediated by the interferon-stimulated genes (ISGs) that lead to the cell-intrinsic immunity. Recently, the overexpression of the bone marrow stromal antigen 2 proteins, also called BST2, Tetherin, or CD317, have been shown to inhibit Morbilliviruses cell to cell fusion in vitro by targeting the H protein [234]. In addition, the interferon-inducible transmembrane protein 1 (IFTIM1) has been shown to inhibit infection by several RNA viruses in vitro .…”

Section: Treatmentsmentioning

confidence: 99%

Measles Encephalitis: Towards New Therapeutics

Ferren

Horvat

Mathieu

2019

Viruses

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Measles remains a major cause of morbidity and mortality worldwide among vaccine preventable diseases. Recent decline in vaccination coverage resulted in re-emergence of measles outbreaks. Measles virus (MeV) infection causes an acute systemic disease, associated in certain cases with central nervous system (CNS) infection leading to lethal neurological disease. Early following MeV infection some patients develop acute post-infectious measles encephalitis (APME), which is not associated with direct infection of the brain. MeV can also infect the CNS and cause sub-acute sclerosing panencephalitis (SSPE) in immunocompetent people or measles inclusion-body encephalitis (MIBE) in immunocompromised patients. To date, cellular and molecular mechanisms governing CNS invasion are still poorly understood. Moreover, the known MeV entry receptors are not expressed in the CNS and how MeV enters and spreads in the brain is not fully understood. Different antiviral treatments have been tested and validated in vitro, ex vivo and in vivo, mainly in small animal models. Most treatments have high efficacy at preventing infection but their effectiveness after CNS manifestations remains to be evaluated. This review describes MeV neural infection and current most advanced therapeutic approaches potentially applicable to treat MeV CNS infection.

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Section: Treatmentsmentioning

confidence: 99%

Measles Encephalitis: Towards New Therapeutics

Ferren

Horvat

Mathieu

2019

Viruses

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“…S2), confirming their suitability for cell-cell fusion experiments. Within our laboratory we have developed cell-cell fusion assays for a number of vGPs [13,15,18,19]; however, the conditions required for fusion are rarely maintained between these proteins. For this study, the mass and ratio of DNA transfected, the length of co-culture, as well as the duration and temperature of nAb incubation, were all conditions that required optimization for hRSV, bRSV, NiV, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 mFITs (Figs S3 and S4).…”

Section: Optimization Of Cell-cell Fusion Assaysmentioning

confidence: 99%

“…In previous studies, we and others have developed assays to reliably quantify cell-cell fusion induced by viruses [9][10][11][12][13][14]. Indeed, these systems have been successfully applied to examine virus host range [15], protein-protein interactions within the attachment complex [16], the mechanism of attachment and entry [11,17], and other biologically relevant questions.…”

Section: Introductionmentioning

confidence: 99%

Micro-fusion inhibition tests: quantifying antibody neutralization of virus-mediated cell–cell fusion

Thakur

Conceicao

Isaacs

et al. 2021

Journal of General Virology

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Although enveloped viruses canonically mediate particle entry through virus–cell fusion, certain viruses can spread by cell–cell fusion, brought about by receptor engagement and triggering of membrane-bound, viral-encoded fusion proteins on the surface of cells. The formation of pathogenic syncytia or multinucleated cells is seen in vivo, but their contribution to viral pathogenesis is poorly understood. For the negative-strand paramyxoviruses respiratory syncytial virus (RSV) and Nipah virus (NiV), cell–cell spread is highly efficient because their oligomeric fusion protein complexes are active at neutral pH. The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has also been reported to induce syncytia formation in infected cells, with the spike protein initiating cell–cell fusion. Whilst it is well established that fusion protein-specific antibodies can block particle attachment and/or entry into the cell (canonical virus neutralization), their capacity to inhibit cell–cell fusion and the consequences of this neutralization for the control of infection are not well characterized, in part because of the lack of specific tools to assay and quantify this activity. Using an adapted bimolecular fluorescence complementation assay, based on a split GFP–Renilla luciferase reporter, we have established a micro-fusion inhibition test (mFIT) that allows the identification and quantification of these neutralizing antibodies. This assay has been optimized for high-throughput use and its applicability has been demonstrated by screening monoclonal antibody (mAb)-mediated inhibition of RSV and NiV fusion and, separately, the development of fusion-inhibitory antibodies following NiV vaccine immunization in pigs. In light of the recent emergence of coronavirus disease 2019 (COVID-19), a similar assay was developed for SARS-CoV-2 and used to screen mAbs and convalescent patient plasma for fusion-inhibitory antibodies. Using mFITs to assess antibody responses following natural infection or vaccination is favourable, as this assay can be performed entirely at low biocontainment, without the need for live virus. In addition, the repertoire of antibodies that inhibit cell–cell fusion may be different to those that inhibit particle entry, shedding light on the mechanisms underpinning antibody-mediated neutralization of viral spread.

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“…This unique topology, with a transmembrane domain at its N-terminus and a GPI anchor at its C-terminus, allows BST2 to act as a bridge between the cell membrane and budding virions, and therefore, BST2 has also been referred to as tetherin [ 314 ]. The ability of BST2 to tether budding virions to the cell membrane is not specific to retroviruses, as BST2 blocks release of several other enveloped viruses, including herpesviruses, filoviruses, VSV and SARS coronavirus [ 315 , 316 , 317 , 318 , 319 , 320 , 321 , 322 , 323 , 324 , 325 ].…”

Section: Retroviral Restriction Factorsmentioning

confidence: 99%

Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

Boso

Kozak

2020

Microorganisms

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The evolutionary conflict between retroviruses and their vertebrate hosts over millions of years has led to the emergence of cellular innate immune proteins termed restriction factors as well as their viral antagonists. Evidence accumulated in the last two decades has substantially increased our understanding of the elaborate mechanisms utilized by these restriction factors to inhibit retroviral replication, mechanisms that either directly block viral proteins or interfere with the cellular pathways hijacked by the viruses. Analyses of these complex interactions describe patterns of accelerated evolution for these restriction factors as well as the acquisition and evolution of their virus-encoded antagonists. Evidence is also mounting that many restriction factors identified for their inhibition of specific retroviruses have broader antiviral activity against additional retroviruses as well as against other viruses, and that exposure to these multiple virus challenges has shaped their adaptive evolution. In this review, we provide an overview of the restriction factors that interfere with different steps of the retroviral life cycle, describing their mechanisms of action, adaptive evolution, viral targets and the viral antagonists that evolved to counter these factors.

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BST2/Tetherin Overexpression Modulates Morbillivirus Glycoprotein Production to Inhibit Cell–Cell Fusion

Cited by 10 publications

References 40 publications

Measles Encephalitis: Towards New Therapeutics

Measles Encephalitis: Towards New Therapeutics

Micro-fusion inhibition tests: quantifying antibody neutralization of virus-mediated cell–cell fusion

Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

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