Anne Bridgen

University of Ulster

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Richard M. Elliott

MRC University of Glasgow Centre for Virus Research

Kurt Tobler

University of Zurich

Mathias Ackermann

University of Zurich

Friedemann Weber

University of Giessen

John K. Fazakerley

Peter Doherty Institute

H.W. Reid

Moredun Research Institute

Michael D. Baron

The Pirbright Institute

Richard E. Randall

University of St Andrews

Barbara Holzer

IMC University of Applied Sciences Krems

Anna Utiger

University of Zurich

Cooperative Institutions

The Pirbright Institute

Moredun Research Institute

University of Glasgow

University of Zurich

University of Edinburgh

Institute of Virology of the Slovak Academy of Sciences

University of Liverpool

MRC University of Glasgow Centre for Virus Research

National Institutes of Health

University of St Andrews

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Reverse genetics of RNA viruses

Oxford University Press eBooks (2000)

Anne Bridgen Rebecca Elliott

Abstract RNA viruses comprise many of the most serious human pathogens. There are now possibly 500 million carriers of hepatitis C virus world-wide (1). Rotavirus infections are responsible for around 18 million cases of severe diarrhoea and nearly 1 million deaths in young children in developing countries annually (2). Measles is still also one of the leading causes of infant death in developing countries, and can induce the rare, but fatal, neurodegenerative disease subacute sclerosing panencephalitis (3). Many human respiratoiy infections are caused by RNA viruses such as influenza, human respiratoiy syncytial virus, coronaviruses, enteroviruses and, one of the most frequent virus pathogens of humans, the rhinoviruses (4). Hantaviruses, members of the Bunyaviridae family, are responsible for haemorrhagic diseases and form one of a number of virus groups whose incidence has increased greatly over the last few years, the so-called ‘emerging viruses’ (5). Perhaps the most frightening of all virus diseases, because of their high mortality and lack of effective prophylaxis and treatment, are those caused by the filoviruses Marburg and Ebola (6).

RNA virus

Subacute sclerosing panencephalitis

10.1093/oso/9780199637171.003.0009

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Citations (2)

Reverse Genetics of RNA Viruses: Applications and Perspectives

Anne Bridgen

Reverse Genetics

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Citations (22)

Identification of the membrane protein of porcine epidemic diarrhea virus

Virus Genes (1995)

Anna Utiger Kurt Tobler Anne Bridgen Mathias Ackermann

Vero cell

Immunogold labelling

10.1007/bf01702594

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Citations (33)

Dugbe virus ovarian tumour domain interferes with ubiquitin/ISG15-regulated innate immune cell signalling

Journal of General Virology (2012)

Siddharth Bakshi Barbara Holzer Anne Bridgen Geoff McMullan Daniel G. Quinn

The ovarian tumour (OTU) domain of the nairovirus L protein has been shown to remove ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host cell proteins, which is expected to have multiple effects on cell signalling pathways. We have confirmed that the OTU domain from the L protein of the apathogenic nairovirus Dugbe virus has deubiquitinating and deISGylating activity and shown that, when expressed in cells, it is highly effective at blocking the TNF-α/NF-κB and interferon/JAK/STAT signalling pathways even at low doses. Point mutations of the catalytic site of the OTU [C40A, H151A and a double mutant] both abolished the ability of the OTU domain to deubiquitinate and deISGylate proteins and greatly reduced its effect on cell signalling pathways, confirming that it is this enzymic activity that is responsible for blocking the two signalling pathways. Expression of the inactive mutants at high levels could still block signalling, suggesting that the viral OTU can still bind to its substrate even when mutated at its catalytic site. The nairovirus L protein is a very large protein that is normally confined to the cytoplasm, where the virus replicates. When the OTU domain was prevented from entering the nucleus by expressing it as part of the N-terminal 205 kDa of the viral L protein, it continued to block type I interferon signalling, but no longer blocked the TNF-α-induced activation of NF-κB.

ISG15

10.1099/vir.0.048322-0

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Citations (24)

The derivation of a restriction endonuclease map forAlcelaphine herpesvirus 1 DNA

Archives of Virology (1991)

Anne Bridgen

Restriction map

Restriction fragment

10.1007/bf01310764

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Bunyamwera bunyavirus nonstructural protein NSs is a nonessential gene product that contributes to viral pathogenesis

Proceedings of the National Academy of Sciences (2001)

Anne Bridgen Friedemann Weber John K. Fazakerley Richard M. Elliott

Bunyamwera virus (family Bunyaviridae , genus Bunyavirus ) contains a tripartite negative-sense RNA genome. The smallest RNA segment, S, encodes the nucleocapsid protein N and a nonstructural protein, NSs, in overlapping reading frames. We have generated a mutant virus lacking NSs, called BUNdelNSs, by reverse genetics. Compared with the wild-type (wt) virus, BUNdelNSs exhibited a smaller plaque size and generated titers of virus approximately 1 log lower. In mammalian cells, the mutant expressed greatly increased levels of N protein; significantly, the marked inhibition of host cell protein synthesis shown by wt virus was considerably impaired by BUNdelNSs. When inoculated by the intracerebral route BUNdelNSs killed BALB/c mice with a slower time course than wt and exhibited a reduced cell-to-cell spread, and titers of virus in the brain were lower. In addition, the abrogation of NSs expression changed Bunyamwera virus from a noninducer to an inducer of an interferon-β promoter. These results suggest that, although not essential for growth in tissue culture or in mice, the bunyavirus NSs protein has several functions in the virus life cycle and contributes to viral pathogenesis.

Sendai virus

RNA virus

Viral Pathogenesis

Viral protein

10.1073/pnas.98.2.664

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Citations (230)

Sequence Analysis of the Porcine Epidemic Diarrhea Virus Genome between the Nucleocapsid and Spike Protein Genes Reveals a Polymorphic ORF

Virology (1994)

Mariela Duarte Kurt Tobler Anne Bridgen Denis Rasschaert Mathias Ackermann

ORFS

Coronavirus

Subgenomic mRNA

Homology

Nidovirales

10.1006/viro.1994.1058

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Citations (122)

Pathogenesis of Dugbe virus infection in wild-type and interferon-deficient mice

Journal of General Virology (2006)

Amanda Boyd John K. Fazakerley Anne Bridgen

In 129 mice, infection with the nairovirus Dugbe virus (DUGV) was lethal following intracerebral but not intraperitoneal inoculation. Following both routes of inoculation, immunostaining of tissue sections demonstrated virus-positive cells in the brain, indicating that DUGV is neuroinvasive in mice. Many brain areas were affected and neurones were the main cell type infected. Infected cells showed punctate accumulations of viral nucleoprotein in the cytoplasm, indicative of virus replication sites. Immunostaining for activated caspase 3 demonstrated no evidence of apoptosis. The type I interferon (IFN) system plays a significant role in defence against DUGV, as 129 IFN-alpha/beta R(-/-) mice died rapidly following both intraperitoneal and intracerebral inoculations. Studies were undertaken to determine whether the IFN-inducible proteins, protein kinase R (PKR) and MxA, were important for protection; neither PKR nor constitutively expressed human MxA played significant roles.

Immunostaining

Nucleoprotein

Pathogenesis

Protein kinase R

Interferon type I

10.1099/vir.0.81767-0

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Citations (25)

Bunyamwera Virus Nonstructural Protein NSs Counteracts Interferon Regulatory Factor 3-Mediated Induction of Early Cell Death

Journal of Virology (2003)

Alain Kohl R. Clayton Friedemann Weber Anne Bridgen Richard E. Randall

ABSTRACT The genome of Bunyamwera virus (BUN; family Bunyaviridae , genus Orthobunyavirus ) consists of three segments of negative-sense RNA. The smallest segment, S, encodes two proteins, the nonstructural protein NSs, which is nonessential for viral replication and transcription, and the nucleocapsid protein N. Although a precise role in the replication cycle has yet to be attributed to NSs, it has been shown that NSs inhibits the induction of alpha/beta interferon, suggesting that it plays a part in counteracting the host antiviral defense. A defense mechanism to limit viral spread is programmed cell death by apoptosis. Here we show that a recombinant BUN that does not express NSs (BUNdelNSs) induces apoptotic cell death more rapidly than wild-type virus. Screening for apoptosis pathways revealed that the proapoptotic transcription factor interferon regulatory factor 3 (IRF-3) was activated by both wild-type BUN and BUNdelNSs infection, but only wild-type BUN was able to suppress signaling downstream of IRF-3. Studies with a BUN minireplicon system showed that active replication induced an IRF-3-dependent promoter, which was suppressed by the NSs protein. In a cell line (P2.1) defective in double-stranded RNA signaling due to low levels of IRF-3, induction of apoptosis was similar for wild-type BUN and BUNdelNSs. These data suggest that the BUN NSs protein can delay cell death in the early stages of BUN infection by inhibiting IRF-3-mediated apoptosis.

10.1128/jvi.77.14.7999-8008.2003

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Citations (97)

Molecular studies of Alcelaphine herpesvirus 1 and the role of the virus in Malignant Catarrhal Fever

Anne Bridgen

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Citations (2)