The Interferon Antagonist NS2 Protein of Respiratory Syncytial Virus Is an Important Virulence Determinant for Humans

Wright, Peter F.; Karron, Ruth A.; Madhi, Shabir А.; Treanor, John J.; King, James C.; O'Shea, Alice; Ikizler, Mine R.; Zhu, Yuwei; Collins, Peter L.; Cutland, Clare; Randolph, Valerie B.; Deatly, Anne M.; Hackell, Jill G.; Gruber, William C.; Murphy, Brian R.

doi:10.1086/499600

Cited by 93 publications

(82 citation statements)

References 34 publications

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“…These pathological changes and clinical symptoms were minimal to absent in the mice that were immunized with attenuated, replication competent PVM strain 15 prior to challenge with virulent parent PVM strain J3666. Our findings are similar to the vaccine-associated reduction in clinical disease and pulmonary pathology is observed in bRSV-vaccinated and challenged cattle [9][10][11]18]. We also observed diminished local production the soluble mediators of inflammation, including MIP-1α, MIP-2, and TNF-α as well as diminished virus replication in effectively vaccinated mice, again similar to the scenario in bRSV-vaccinated cattle [9][10][11].…”

Section: Discussionsupporting

confidence: 87%

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Mucosal inoculation with an attenuated mouse pneumovirus strain protects against virulent challenge in wild type and interferon-gamma receptor deficient mice

Ellis

Martin

Waldner

et al. 2007

Vaccine

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Protective mechanisms underlying the responses to mucosal vaccination are not yet clearly defined. Using the natural mouse pneumovirus pathogen, pneumonia virus of mice (PVM), we explore responses of wild type and interferon-gamma (IFNγ) receptor gene-deleted mice to virulent challenge after mucosal vaccination with an attenuated virus strain. Serum neutralizing antibodies develop after intranasal inoculation with 30 pfu of attenuated, replication-competent PVM strain 15, which correlate with diminished gross and microscopic pulmonary pathology and protection from weight loss in response to subsequent challenge with the virulent parent PVM strain J3666. Virus replication in response to challenge was blunted in PVM strain 15 vaccinated mice, as was local production of secretory mediators IFNγ, TNF-α, MIP-1α, and MIP-2. Interestingly, responses of vaccinated IFNγ receptor gene-deleted mice were indistinguishable from those of the wild type, suggesting that IFNγ signaling may not be crucial for the generation of adaptive responses to pneumovirus infection in vivo. (150 words).

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Section: Discussionsupporting

confidence: 87%

“…These live-attenuated viruses include cold-passaged temperature sensitive mutations with additional changes introduced into what are considered to be non-essential virus genes (NS1, NS2 or SH). Vaccines with both NS2 and SH deletions have been documented as safe in clinical trials [17][18].…”

Section: Introductionmentioning

confidence: 99%

Mucosal inoculation with an attenuated mouse pneumovirus strain protects against virulent challenge in wild type and interferon-gamma receptor deficient mice

Ellis

Martin

Waldner

et al. 2007

Vaccine

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“…There are a number of examples where such an approach has been, or is being, tried, e.g. influenza virus (Talon et al, 2000b;Ferko et al, 2004;Fernandez-Sesma et al, 2006;Richt et al, 2006), paramyxoviruses (Teng et al, 2000;Valarcher et al, 2003;Bartlett et al, 2006;Van Cleve et al, 2006;Wright et al, 2006), BUNV (Weber et al, 2002), EBOV (Hartman et al, 2006) and flaviruses . However, there are a number of difficulties in using IFN-sensitive viruses as vaccines.…”

Section: Ifn-sensitive Viruses As Attenuated Virus Vaccinesmentioning

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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“…Several live-attenuated RSV vaccine candidates have been developed by conventional cold passage and/or chemical mutagenesis (cpts RSV strains) and evaluated in a clinical setting (35,36). Second-generation live-http://bmbreports.org attenuated RSV has been also generated by reverse genetics (rA2cp strains) and tested in RSV-naïve 1-2 month-old infants, showing that protective immunity could be achieved in a majority of the recipients (37,38). However, for this live-attenuated RSV approach, it is quite challenging to determine whether or not the balance between over-attenuation and under-attenuation is most appropriate for a safe and effective vaccine.…”

Section: Current Rsv Vaccine Strategiesmentioning

confidence: 99%

Current progress on development of respiratory syncytial virus vaccine

Chang

2011

BMB Reports

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The Interferon Antagonist NS2 Protein of Respiratory Syncytial Virus Is an Important Virulence Determinant for Humans

Cited by 93 publications

References 34 publications

Mucosal inoculation with an attenuated mouse pneumovirus strain protects against virulent challenge in wild type and interferon-gamma receptor deficient mice

Mucosal inoculation with an attenuated mouse pneumovirus strain protects against virulent challenge in wild type and interferon-gamma receptor deficient mice

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

Current progress on development of respiratory syncytial virus vaccine

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