Respiratory syncytial virus nonstructural protein 2 specifically inhibits type I interferon signal transduction

-Bovine respiratory syncytial virus (BRSV) belongs to the pneumovirus genus within the family Paramyxoviridae and is a major cause of respiratory disease in young calves. BRSV is enveloped and contains a negative sense, single-stranded RNA genome encoding 11 proteins. The virus replicates predominantly in ciliated respiratory epithelial cells but also in type II pneumocytes. It appears to cause little or no cytopathology in ciliated epithelial cell cultures in vitro, suggesting that much of the pathology is due to the host's response to virus infection. RSV infection induces an array of pro-inflammatory chemokines and cytokines that recruit neutrophils, macrophages and lymphocytes to the respiratory tract resulting in respiratory disease. Although the mechanisms responsible for induction of these chemokines and cytokines are unclear, studies on the closely related human (H)RSV suggest that activation of NF-κB via TLR4 and TLR3 signalling pathways is involved. An understanding of the mechanisms by which BRSV is able to establish infection and induce an inflammatory response has been facilitated by advances in reverse genetics, which have enabled manipulation of the virus genome. These studies have demonstrated an important role for the non-structural proteins in anti-interferon activity, a role for a virokinin, released during proteolytic cleavage of the fusion protein, in the inflammatory response and a role for the SH and the secreted form of the G protein in establishing pulmonary infection. Knowledge gained from these studies has also provided the opportunity to develop safe, stable, live attenuated virus vaccine candidates.

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“…3). In addition, the HRSV NS proteins inhibit IFNα/β signalling by inducing a decrease in Stat2 expression [87,106] (Fig. 3).…”

Section: The Role Of the Ns Proteins In The Pathogenesis Of Brsvmentioning

confidence: 99%

Bovine respiratory syncytial virus infection

Valarcher¹,

2007

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“…We and others [16][17][18][19][20][21][22][23][24][25][26][27][28][29] have recently shown that NS1 and NS2 inhibit and/or degrade a number of proteins of the IFN induction and response pathways. We have since screened other members of these pathways, confirmed and extended the repertoire of NS targets to include: RIG-I, TRAF3, IKKε, IRF3, IRF7 and STAT2 ( Figure 1A).…”

Section: An Expanding List Of Cellular Innate Immune Proteins Targetementioning

confidence: 99%

“…With the sole exception of pneumoviruses, members of this family produce IFN-suppressor proteins such as V, W and C through co-transcriptional RNA editing of the viral P gene [10,[13][14][15]. Pneumoviruses, represented by RSV, do not use RNA editing; instead, they uniquely encode two nonstructural (NS) proteins, NS1 and NS2, which strongly suppress both IFN induction and IFNresponse pathways by inhibiting or degrading a number of signaling proteins involved in these two pathways [16][17][18][19][20][21][22][23][24][25][26][27][28][29], and thus act as essential virulence factors [30][31][32]. In pursuing the mechanism by which the NS proteins target such a diverse array of immune proteins that share little or no sequence identity, we wondered whether there is a common location of NS proteins and their targets.…”

Section: Introductionmentioning

confidence: 99%

Viral degradasome hijacks mitochondria to suppress innate immunity

et al. 2013

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The balance between the innate immunity of the host and the ability of a pathogen to evade it strongly influences pathogenesis and virulence. The two nonstructural (NS) proteins, NS1 and NS2, of respiratory syncytial virus (RSV) are critically required for RSV virulence. Together, they strongly suppress the type I interferon (IFN)-mediated innate immunity of the host cells by degrading or inhibiting multiple cellular factors required for either IFN induction or response pathways, including RIG-I, IRF3, IRF7, TBK1 and STAT2. Here, we provide evidence for the existence of a large and heterogeneous degradative complex assembled by the NS proteins, which we named "NS-degradasome" (NSD). The NSD is roughly ~300-750 kD in size, and its degradative activity was enhanced by the addition of purified mitochondria in vitro. Inside the cell, the majority of the NS proteins and the substrates of the NSD translocated to the mitochondria upon RSV infection. Genetic and pharmacological evidence shows that optimal suppression of innate immunity requires mitochondrial MAVS and mitochondrial motility. Together, we propose a novel paradigm in which the mitochondria, known to be important for the innate immune activation of the host, are also important for viral suppression of the innate immunity.

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“…Numerous Paramyxovirus family members inhibit IFN signaling in epithelial cells through inhibition of STAT phosphorylation (26), proteasomal degradation of STAT proteins (27)(28)(29)(30), sequestration of STAT proteins in high-molecular weight complexes (31,32), and inhibition of nuclear localization of STAT proteins (33). Specifically, RSV inhibits type I IFN signaling in the respiratory epithelium through the proteasomal degradation of STAT2, a mechanism that is dependent on the expression of the RSV NS2 protein (27,34). Although it is clear that RSV inhibits IFN signaling in the epithelium, it is currently unclear whether and by what mechanisms RSV inhibits the macrophage type I IFN and type II IFN response.…”

Section: Abstract: Macrophages; Ifn; Signal Transduction; Transcriptimentioning

confidence: 99%

“…Although the capacity of RSV-encoded mechanisms to inhibit IFN-mediated signaling in epithelial cells is well documented (27,30,34,37), the ability of RSV to infect macrophages and modulate their response to IFN-a/b or IFN-g signaling has not been extensively investigated. To initially test the ability of RSV to subvert IFN-mediated responses, IFN-b-responsive pISREluciferase and IFN-g-responsive pGAS-luciferase reporter assays were used to assess transactivation of ISRE-and GAS-modulated gene products.…”

Section: Rsv Inhibits Type I Ifn-and Type Ii Ifn-inducible Transcriptmentioning

confidence: 99%

Respiratory Syncytial Virus Impairs Macrophage IFN-α/β– and IFN-γ–Stimulated Transcription by Distinct Mechanisms

Senft

Taylor

Lei

et al. 2010

Am J Respir Cell Mol Biol

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Macrophages are the primary lung phagocyte and are instrumental in maintenance of a sterile, noninflamed microenvironment. IFNs are produced in response to bacterial and viral infection, and activate the macrophage to efficiently counteract and remove pathogenic invaders. Respiratory syncytial virus (RSV) inhibits IFN-mediated signaling mechanisms in epithelial cells; however, the effects on IFN signaling in the macrophage are currently unknown. We investigated the effect of RSV infection on IFN-mediated signaling in macrophages. RSV infection inhibited IFN-b-and IFN-g-activated transcriptional mechanisms in primary alveolar macrophages and macrophage cell lines, including the transactivation of important Nod-like receptor family genes, Nod1 and class II transactivator. RSV inhibited IFN-b-and IFN-g-mediated transcriptional activation by two distinct mechanisms. RSV impaired IFN-b-mediated signal transducer and activator of transcription (STAT)-1 phosphorylation through a mechanism that involves inhibition of tyrosine kinase 2 phosphorylation. In contrast, RSV-impaired transcriptional activation after IFN-g stimulation resulted from a reduction in the nuclear STAT1 interaction with the transcriptional coactivator, CBP, and was correlated with increased phosphorylation of STAT1b, a dominantnegative STAT1 splice variant, in response to IFN-g. In support of this concept, overexpression of STAT1b was sufficient to repress the IFNg-mediated expression of class II transactivator. These results demonstrate that RSV inhibits IFN-mediated transcriptional activation in macrophages, and suggests that paramyxoviruses modulate an important regulatory mechanism that is critical in linking innate and adaptive immune mechanisms after infection. Keywords: macrophages; IFN; signal transduction; transcriptional activationRespiratory syncytial virus (RSV) is an important causative agent of severe respiratory tract infections in pediatric, immunocompromised, and elderly populations (1-5). RSV infection elicits a poor adaptive immune response; therefore, infections occur repeatedly throughout life (6, 7). This common paramyxovirus has also been associated with secondary bacterial infections of the lung (3, 8-10); however, as with other viralinduced secondary bacterial infections, the underlying mechanisms are not well understood.IFN-a and IFN-b (type I) and IFN-g (type II) are produced in the lung in response to microbial infection, and are potent activators of macrophage innate antimicrobial immunity; they also induce pathways that promote efficient antigen processing and presentation to cells of the adaptive immune system (11, 12). The requirement of IFN for the efficient clearance of pathogens is evident in IFN-b 2/2 , IFN-g 2/2 , IFN-a receptor 2/2 , and IFN-g receptor 2/2 mice, as these mice, lacking IFN signaling, display severe impairment in natural resistance to a variety of viral, bacterial, and parasitic infections (13-20). IFN-a or IFN-b ligation of the IFN-a/b receptor results in the phosphorylation and activation of the ...

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Respiratory syncytial virus nonstructural protein 2 specifically inhibits type I interferon signal transduction

Cited by 138 publications

References 53 publications

Bovine respiratory syncytial virus infection

Bovine respiratory syncytial virus infection

Viral degradasome hijacks mitochondria to suppress innate immunity

Respiratory Syncytial Virus Impairs Macrophage IFN-α/β– and IFN-γ–Stimulated Transcription by Distinct Mechanisms

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