Respiratory syncytial virus inhibits interferon-α-inducible signaling in macrophage-like U937 cells

Zhao, Dongchi; Tang, Yan; Li, Lei; Shangyou, You; Zhang, Chuyu

doi:10.1016/j.jinf.2006.06.005

Cited by 22 publications

(19 citation statements)

References 27 publications

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“…Influenza A virus (47,52), RSV (24,79), and HBV (30,72) (Table 1) are just a few examples of viruses that benefit in this manner by exploiting SOCS protein function. It is likely that the discovery of others will soon follow.…”

Section: Virally Exploited Functions Of Socs Proteinsmentioning

confidence: 99%

“…However, differences in the ability of RSV to productively infect cells of the monocyte/macrophage lineage have been tied to SOCS expression. While RSV can induce the expression of SOCS1, SOCS3, and CIS and establish a successful infection in macrophages (phorbol myristate acetate [PMA]-differentiated U937 cells), it is not capable of SOCS expression or infection in monocytes (undifferentiated U937 cells) (79). A subsequent report showed that knockdown of any of these SOCS proteins in cells susceptible to infection resulted in an increase in STAT1/2 phosphorylation and expression of the IFN-induced antiviral target gene OAS, as well as a correlating decrease in RSV replication (24).…”

Section: Effects Of Socs Expression On Viral Diseasementioning

confidence: 99%

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Viral Exploitation of Host SOCS Protein Functions

Akhtar

Benveniste

2011

J Virol

111

102

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Over the past decade, a family of host proteins known as suppressors of cytokine signaling (SOCS) have emerged as frequent targets of viral exploitation. Under physiologic circumstances, SOCS proteins negatively regulate inflammatory signaling pathways by facilitating ubiquitination and proteosomal degradation of pathway machinery. Their expression is tightly regulated to prevent excessive inflammation while maintaining protective antipathogenic responses. Numerous viruses, however, have developed mechanisms to induce robust host SOCS protein expression following infection, essentially "hijacking" SOCS function to promote virus survival. To date, SOCS proteins have been shown to inhibit protective antiviral signaling pathways, allowing viruses to evade the host immune response, and to ubiquitinate viral proteins, facilitating intracellular viral trafficking and progeny virus assembly. Importantly, manipulation of SOCS proteins not only facilitates progression of the viral life cycle but also powerfully shapes the presentation of viral disease. SOCS proteins can define host susceptibility to infection, contribute to peripheral disease manifestations such as immune dysfunction and cancer, and even modify the efficacy of therapeutic interventions. Looking toward the future, it is clear that a better understanding of the role of SOCS proteins in viral diseases will be essential in our struggle to modulate and even eliminate the pathogenic effects of viruses on the host.

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Section: Virally Exploited Functions Of Socs Proteinsmentioning

confidence: 99%

Section: Effects Of Socs Expression On Viral Diseasementioning

confidence: 99%

Viral Exploitation of Host SOCS Protein Functions

Akhtar

Benveniste

2011

J Virol

111

102

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“…In vitro, RSV induces a lower level of interferon (IFN) and interferes with type I IFN signaling by degrading the signal transducer and activator of transcription (STAT)2 protein and inhibiting STAT2 phosphorylation [9,10,11,12]. Recombinant RSV mutants lacking NS1 and NS2 cause marked production of host IFN-α and -β, highlighting the importance of these proteins in resisting the innate antiviral response [7,8].…”

Section: Introductionmentioning

confidence: 99%

Respiratory Syncytial Virus NS1 Protein Degrades STAT2 by Inducing SOCS1 Expression

Xu¹,

Zheng²,

Zheng³

et al. 2014

Intervirology

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Objectives: Respiratory syncytial virus (RSV) nonstructural protein NS1 (NS1) has been shown to block interferon (IFN)-inducible antiviral signaling. The suppressor of cytokine signaling (SOCS) gene family could utilize a feedback loop to block the activation of the JAK/STAT signaling pathway, further inhibiting the activation of host type I IFN. We evaluated the role of the SOCS1 and SOCS3 genes in this antiviral mechanism. Material and Methods: A humanized stable NS1 (rich in GC)-expressing plasmid was constructed, and A549 cells were transfected with it. Expression of the SOCS1, SOCS3, RIG-I, and TLR3 mRNAs was measured with real-time PCR. STAT2 and pSTAT2 expression was determined with Western blotting. Results: RSV NS1 upregulated SOCS1 mRNA expression 30-fold increase compared with the baseline level in very early phase (p < 0.01), and silence of RIG-I or TLR3 mRNA did not affect NS1-induced SOCS1 expression. NS1 inhibited IFN-α-induced STAT2 phosphorylation and degraded STAT2 in a time-dependent manner compared with the empty-vector control (p < 0.05). Conclusion: RSV NS1 upregulates SOCS1 expression in a RIG-I- and TLR3-independent pathway, to inhibit STAT2 phosphorylation.

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“…Although SOCS3 has been shown previously to modulate innate immune responses to both DNA and RNA viruses (34,(49)(50)(51), a role for SOCS3 in enhancing EBOV VP40 ubiquitinylation leading to efficient VLP egress was previously undescribed. In addition, our findings provide new insights into innate immune interactions with key structural proteins of EBOV and suggest novel mechanisms of action by which SOCS3 may influence pathogenesis and immune evasion.…”

Section: Discussionmentioning

confidence: 99%

Suppressor of Cytokine Signaling 3 Is an Inducible Host Factor That Regulates Virus Egress during Ebola Virus Infection

Okumura

Rasmussen

Halfmann

et al. 2015

J Virol

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Ebola virus (EBOV) initially targets monocytes and macrophages, which can lead to the release of proinflammatory cytokines and chemokines. These inflammatory cytokines are thought to contribute to the development of circulatory shock seen in fatal EBOV infections. The VP40 matrix protein is a key viral structural protein that is critical for virion egress. Physical and functional interactions between VP40 and host proteins such as Tsg101 and Nedd4 facilitate efficient release of VP40-driven viruslike particles (VLPs) and infectious virus. Here, we show that host suppressor of cytokine signaling 3 (SOCS3) can also bind to EBOV VP40, leading to enhanced ubiquitinylation and egress of VP40. Indeed, titers of infectious EBOV derived from SOCS3 knockout mouse embryonic fibroblasts (MEFs) were significantly reduced compared to those from wild-type (WT) MEFs at 24 and 48 h postinfection. Importantly, this reduced virus yield could be rescued back to WT levels by exogenously expressing SOCS3. Lastly, we show that SOCS3 expression is induced by EBOV glycoprotein (GP) expression and that VLPs containing EBOV VP40 and GP induced production of proinflammatory cytokines, which induced SOCS3 for negative-feedback regulation. These data indicate that host innate immune protein SOCS3 may play an important role in budding and pathogenesis of EBOV. IMPORTANCEThe VP40 matrix protein is a key structural protein critical for Ebola virus budding. Physical and functional interactions between VP40 and host proteins such as Tsg101 and Nedd4 facilitate efficient release of VLPs and infectious virus. We reported that host TLR4 is a sensor for Ebola GP on VLPs and that the resultant TLR4 signaling pathways lead to the production of proinflammatory cytokines. Host SOCS3 regulates the innate immune response by controlling and limiting the proinflammatory response through negative-feedback inhibition of cytokine receptors. We present evidence that Ebola virus VLPs stimulate induction of SOCS3 as well as proinflammatory cytokines, and that expression of human SOCS3 enhances budding of Ebola VLPs and infectious virus via a mechanism linked to the host ubiquitinylation machinery. E bola and Marburg viruses are emerging human pathogens within the Filoviridae family and are considered potential agents of bioterrorism. To date, there are no approved vaccines or therapeutics to prevent or treat filovirus infections in humans. Severe hemorrhagic disease caused by filoviruses are characterized by generalized fluid distribution problems, hypotension, coagulation disorders, and fulminant shock (1). Ebola virus (EBOV) first targets monocytes/macrophages and dendritic cells (DCs), leading to the release of proinflammatory cytokines and chemokines, including tumor necrosis factor (TNF), interleukin-1␤ (IL-1␤), macrophage inflammatory protein 1␣ (MIP-1␣), and reactive oxygen and nitrogen species (1, 2). An investigation of the interactions between EBOV proteins and host innate immune proteins may provide new insights into EBOV pathogenesis and uncov...

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Respiratory syncytial virus inhibits interferon-α-inducible signaling in macrophage-like U937 cells

Cited by 22 publications

References 27 publications

Viral Exploitation of Host SOCS Protein Functions

Viral Exploitation of Host SOCS Protein Functions

Respiratory Syncytial Virus NS1 Protein Degrades STAT2 by Inducing SOCS1 Expression

Suppressor of Cytokine Signaling 3 Is an Inducible Host Factor That Regulates Virus Egress during Ebola Virus Infection

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