La Crosse Bunyavirus Nonstructural Protein NSs Serves To Suppress the Type I Interferon System of Mammalian Hosts

Blakqori, Gjon; Delhaye, Sophie; Habjan, Matthias; Blair, Carol D.; Sánchez-Vargas, Irma; Olson, Ken E.; Attarzadeh-Yazdi, Ghassem; Atkinson, Barry; Kohl, Alain; Kalinke, Ulrich; Weiß, Siegfried; Michiels, Thomas; Staeheli, Peter; Weber, Friedemann

doi:10.1128/jvi.01933-06

Cited by 167 publications

(197 citation statements)

References 59 publications

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“…However, a recombinant BUNV that does not encode a NSs protein is pathogenic in IFN-a/b receptor-knockout mice and grows to high titres in cells that do not produce IFN (Weber et al, 2002;Young et al, 2003). Similarly, the NSs protein of La Crosse virus (LACV) serves primarily to suppress the IFN response of mammalian hosts (Blakqori et al, 2007). A mutation in the VSV matrix (M) protein (which, in wild-type virus, causes a general inhibition of host-cell transcription and translation) also leads to an attenuated virus with efficient IFN-b-inducing properties (Ferran & Lucas-Lenard, 1997).…”

Section: General Considerations Of How Viruses Evade the Ifn Responsementioning

confidence: 99%

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

Randall

Goodbourn

2008

Journal of General Virology

1,394

1,420

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The interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. & Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer. Biology of the interferon systemThe interferons (IFNs) are a group of secreted cytokines that elicit distinct antiviral effects. They are grouped into three classes called type I, II and III IFNs, according to their amino acid sequence. Type I IFNs (discovered in 1957;Isaacs & Lindenmann, 1957) comprise a large group of molecules; mammals have multiple distinct IFN-a genes (13 in man), one to three IFN-b genes (one in man) and other genes, such as IFN-v, -e, -t, -d and -k. The IFN-a and -b genes are induced directly in response to viral infection, whereas IFN-v, -e, -d and -k play less well-defined roles, such as regulators of maternal recognition in pregnancy. Thus, rather than use the term 'type I IFN', we will use IFN-a/b when referring to the virally induced cytokines. Although the multigenic nature of IFN-a has been known for over 20 years, the significance of this is still debatedi.e. whether these genes are expressed differentially in distinct cell types, whether they are inducible by different types of viruses or whether they are functionally specialized (Brideau-Andersen et al., 2007). For the rest of this review, we will not distinguish between IFN-a subtypes. Type III IFNs have been described more recently and comprise IFNl1, -l2 and -l3, also referred to as IL-2...

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Section: General Considerations Of How Viruses Evade the Ifn Responsementioning

confidence: 99%

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

Randall

Goodbourn

2008

Journal of General Virology

1,394

1,420

View full text Add to dashboard Cite

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“…The NSs-deficient mutant of La Crosse virus has previously been described (20,21). Newcastle disease virus (NDV)-containing allantoidal fluid was purchased from Lohmann Tierzucht.…”

Section: Virusesmentioning

confidence: 99%

Novel Reporter Mouse Reveals Constitutive and Inflammatory Expression of IFN-β In Vivo

Lienenklaus

Cornitescu²,

Zie̜tara³

et al. 2009

The Journal of Immunology

Self Cite

216

250

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Type I IFN is a major player in innate and adaptive immune responses. Besides, it is involved in organogenesis and tumor development. Generally, IFN responses are amplified by an autocrine loop with IFN-β as the priming cytokine. However, due to the lack of sensitive detection systems, where and how type I IFN is produced in vivo is still poorly understood. In this study, we describe a luciferase reporter mouse, which allows tracking of IFN-β gene induction in vivo. Using this reporter mouse, we reveal strong tissue-specific induction of IFN-β following infection with influenza or La Crosse virus. Importantly, this reporter mouse also allowed us to visualize that IFN-β is expressed constitutively in several tissues. As suggested before, low amounts of constitutively produced IFN might maintain immune cells in an activated state ready for a timely response to pathogens. Interestingly, thymic epithelial cells were the major source of IFN-β under noninflammatory conditions. This relatively high constitutive expression was controlled by the NF Aire and might influence induction of tolerance or T cell development.

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Section: Introductionmentioning

confidence: 99%

“…Secreted IFN binds to the IFN receptor and activates a JAK/STAT signalling pathway, upregulating the expression of a subset of genes that impede virus replication (Randall & Goodbourn, 2008). However, many viruses have evolved mechanisms to circumvent the IFN response (Blakqori et al, 2007;Jennings et al, 2005;Kopecky-Bromberg et al, 2007;Narayanan et al, 2008).Porcine reproductive and respiratory syndrome virus (PRRSV), the causative agent of porcine reproductive and respiratory syndrome, is a small enveloped, singlestranded, positive-sense RNA virus belonging to the family Arteriviridae within the order Nidovirales (Meulenberg, 2000). The genome is about 15.4 kb and contains at least nine ORFs.…”

mentioning

confidence: 99%

The cysteine protease domain of porcine reproductive and respiratory syndrome virus non-structural protein 2 antagonizes interferon regulatory factor 3 activation

Zheng

Zhou

et al. 2010

Journal of General Virology

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There is growing evidence that porcine reproductive and respiratory syndrome virus (PRRSV) has developed mechanisms to subvert the host innate immune response. PRRSV non-structural protein 2 (Nsp2) was suggested previously as a potential interferon (IFN) antagonist. This study focused on Nsp2 to investigate its inhibitory mechanism of IFN induction. It was demonstrated that Nsp2 strongly inhibited IFN-b production by antagonizing activation of the IFN regulatory factor 3 (IRF-3) pathway induced by the Sendai virus (SeV). Further studies revealed that the cysteine protease domain (PL2) of Nsp2 was necessary for IFN antagonism. Additionally, both full-length Nsp2 and the PL2 protease domain of Nsp2 were found to inhibit SeV-induced phosphorylation and nuclear translocation of IRF-3. These findings suggest that Nsp2 is likely to play an important role in subversion of IRF-3-dependent innate antiviral defences, providing a basis for elucidating the mechanisms underlying PRRSV pathogenesis. INTRODUCTIONThe production of type I interferons (IFN-a/b) plays a pivotal role in the host antiviral immune defence (Bonjardim, 2005). Cellular sensors capable of recognizing various viral determinants initiate IFN signal transduction. Positive-stranded RNA viruses can generate intermediate dsRNA during replication, which is an efficient inducer of type I IFNs. This intermediate dsRNA can trigger a cascade of cellular sensors, resulting in type I IFN production and secretion (Kawai & Akira, 2006a;Randall & Goodbourn, 2008). The induction of type I IFNs is initiated via recognition of a pathogen-associated molecule in dsRNA by cellular pattern recognition receptors, including Tolllike receptor 3 (TLR3), caspase recruitment domain (CARD)-containing proteins, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 . TLR3 signals through the adaptor molecule Toll-interleukin-1-resistance domain-containing adaptor inducing IFN-b (TRIF), whilst MDA-5 and RIG-I signal through the adaptor molecule mitochondrial antiviral signal protein (MAVS; also known as IPS-1, Cardif and VISA) to activate a type I IFN response (Kawai & Akira, 2006b; Kawai et al., 2005; Yamamoto et al., 2003). Despite utilizing different adaptors, both pathways converge to activate two downstream kinases, TANK-binding kinase 1 (TBK-1) and inhibitor of kB kinase e (IKKe), subsequently leading to the activation of latent IFN transcription factors, including IFN regulatory factors (IRF-3 and/or IRF-7), nuclear factor-kB (NF-kB) and activating protein 1 (AP-1) (Fitzgerald et al., 2003;Randall & Goodbourn, 2008; Sharma et al., 2003). Activated IFN transcription factors translocate to the nucleus and activate IFN transcription (Biron, 2001). Secreted IFN binds to the IFN receptor and activates a JAK/STAT signalling pathway, upregulating the expression of a subset of genes that impede virus replication (Randall & Goodbourn, 2008). However, many viruses have evolved mechanisms to circumvent the IFN response (Blakqori et al., 2007;Jennings et al.,...

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La Crosse Bunyavirus Nonstructural Protein NSs Serves To Suppress the Type I Interferon System of Mammalian Hosts

Abstract: La Crosse virus (LACV) is a mosquito-transmitted member of the

Cited by 167 publications

References 59 publications

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

Novel Reporter Mouse Reveals Constitutive and Inflammatory Expression of IFN-β In Vivo

The cysteine protease domain of porcine reproductive and respiratory syndrome virus non-structural protein 2 antagonizes interferon regulatory factor 3 activation

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