scholarly journals Rotavirus NSP1 Inhibits Expression of Type I Interferon by Antagonizing the Function of Interferon Regulatory Factors IRF3, IRF5, and IRF7

2007 ◽  
Vol 81 (9) ◽  
pp. 4473-4481 ◽  
Author(s):  
Mario Barro ◽  
John T. Patton
Keyword(s):  
Mammalian Cells ◽  
Type I Interferon ◽  
Common Element ◽  
Type I ◽  
Wild Type ◽  
Regulatory Factor ◽  
Poor Growth ◽  
Infected Cells ◽  
Growth Phenotype ◽  
Dependent Processes

ABSTRACT Secretion of interferon (IFN) by virus-infected cells is essential for activating autocrine and paracrine pathways that promote cellular transition to an antiviral state. In most mammalian cells, IFN production is initiated by the activation of constitutively expressed IFN regulatory factor 3, IRF3, which in turn leads to the induction of IRF7, the “master regulator” of IFN type I synthesis (alpha/beta IFN). Previous studies established that rotavirus NSP1 antagonizes IFN signaling by inducing IRF3 degradation. In the present study, we have determined that, in comparison to wild-type rotaviruses, rotaviruses encoding defective NSP1 grow to lower titers in some cell lines and that this poor growth phenotype is due to their failure to suppress IFN expression. Furthermore, we provide evidence that rotaviruses encoding wild-type NSP1 subvert IFN signaling by inducing the degradation of not only IRF3, but also IRF7, with both events occurring through proteasome-dependent processes that proceed with similar efficiencies. The capacity of NSP1 to induce IRF7 degradation may allow rotavirus to move across the gut barrier by enabling the virus to replicate in specialized trafficking cells (dendritic cells and macrophages) that constitutively express IRF7. Along with IRF3 and IRF7, NSP1 was found to induce the degradation of IRF5, a factor that upregulates IFN expression and that is involved in triggering apoptosis during viral infection. Our analysis suggests that NSP1 mediates the degradation of IRF3, IRF5, and IRF7 by recognizing a common element of IRF proteins, thereby allowing NSP1 to act as a broad-spectrum antagonist of IRF function.

scholarly journals Differential Inhibition of Type I Interferon Induction by Arenavirus Nucleoproteins

2007 ◽  
Vol 81 (22) ◽  
pp. 12696-12703 ◽  
Author(s):  
Luis Martínez-Sobrido ◽  
Panagiotis Giannakas ◽  
Beatrice Cubitt ◽  
Adolfo García-Sastre ◽  
Juan Carlos de la Torre
Keyword(s):  
New World ◽  
Nuclear Translocation ◽  
Type I Interferon ◽  
Lymphocytic Choriomeningitis ◽  
Interferon Response ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Induction ◽  
Tacaribe Virus ◽  
Infected Cells

ABSTRACT We have documented that the nucleoprotein (NP) of the prototypic arenavirus lymphocytic choriomeningitis virus is an antagonist of the type I interferon response. In this study we tested the ability of NPs encoded by representative arenavirus species from both Old World and New World antigenic groups to inhibit production of interferon. We found that, with the exception of Tacaribe virus (TCRV), all NPs tested inhibited activation of beta interferon and interferon regulatory factor 3 (IRF-3)-dependent promoters, as well as the nuclear translocation of IRF-3. Consistent with this observation, TCRV-infected cells also failed to inhibit interferon production.

scholarly journals Human Rhinovirus Attenuates the Type I Interferon Response by Disrupting Activation of Interferon Regulatory Factor 3

2006 ◽  
Vol 80 (10) ◽  
pp. 5021-5031 ◽  
Author(s):  
Tao Peng ◽  
Swathi Kotla ◽  
Roger E. Bumgarner ◽  
Kurt E. Gustin
Keyword(s):  
Type I Interferon ◽  
Transcriptional Response ◽  
Interferon Regulatory Factor ◽  
Alveolar Epithelial Cells ◽  
Interferon Response ◽  
Type I ◽  
Regulatory Factor ◽  
Full Spectrum ◽  
Interferon Regulatory Factor 3 ◽  
Infected Cells

ABSTRACT The type I interferon (IFN) response requires the coordinated activation of the latent transcription factors NF-κB, interferon regulatory factor 3 (IRF-3), and ATF-2, which in turn activate transcription from the IFN-β promoter. Synthesis and subsequent secretion of IFN-β activate the Jak/STAT signaling pathway, resulting in the transcriptional induction of the full spectrum of antiviral gene products. We utilized high-density microarrays to examine the transcriptional response to rhinovirus type 14 (RV14) infection in HeLa cells, with particular emphasis on the type I interferon response and production of IFN-β. We found that, although RV14 infection results in altered levels of a wide variety of host mRNAs, induction of IFN-β mRNA or activation of the Jak/STAT pathway is not seen. Prior work has shown, and our results have confirmed, that NF-κB and ATF-2 are activated following infection. Since many viruses are known to target IRF-3 to inhibit the induction of IFN-β mRNA, we analyzed the status of IRF-3 in infected cells. IRF-3 was translocated to the nucleus and phosphorylated in RV14-infected cells. Despite this apparent activation, very little homodimerization of IRF-3 was evident following infection. Similar results in A549 lung alveolar epithelial cells demonstrated the biological relevance of these findings to RV14 pathogenesis. In addition, prior infection of cells with RV14 prevented the induction of IFN-β mRNA following treatment with double-stranded RNA, indicating that RV14 encodes an activity that specifically inhibits this innate host defense pathway. Collectively, these results indicate that RV14 infection inhibits the host type I interferon response by interfering with IRF-3 activation.

Abstract 1407: Interferon Regulatory Factor-9 (irf-9) Mediates Short Term Host Protection, But Promotes Long Term Immune Injury In Evolution Of Myocarditis Leading To Dilated Cardiomyopathy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Michael Konviser ◽  
Youan Liu ◽  
Manyin Chen ◽  
Yu Shi ◽  
Mei Sun ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Cardiac Hypertrophy ◽  
Type I Interferon ◽  
Interferon Regulatory Factor ◽  
Acquired Immunity ◽  
Type I ◽  
Interferon Production ◽  
Wild Type ◽  
Regulatory Factor ◽  
Host Protection

INTRODUCTION: Evolution of viral myocarditis to dilated cardiomyopathy (DCM) represents a delicate balance between host innate immunity and T-cell acquired immunity. IRF-9 is a key member of a transcription factor family that regulates type I interferon (IFN) production, critical for innate antiviral protection. However, the influence of innate immunity in general and IRF-9 in particular on acquired immunity and DCM is unknown. HYPOTHESIS: IRF-9 signaling provides immediate host protection through interferon production, but stimulates acquired immunity leading to DCM in a coxsackievirus murine myocarditis model. METHODS: Interferon-regulatory factor 9 (IRF-9) homozygous knockout mice were generated, and show impaired type I interferon production. Wild-type (WT, n=51) and IRF-9 −/− (n=124) littermates were inoculated with 10^2 p.f.u. of coxsackievirus B3 as previously described. Survival, viral titers, cardiac hypertrophy, inflammation and fibrosis were evaluated on days 0, 4, 7, 10, 14, 28 and 42. Splenocyte subpopulations were cell sorted and quantitated by FACS. RESULTS: IRF9−/− mice showed dramatically increased mortality compared to the wild-type littermates (0% WT vs 72% IRF-9 −/− on day 14, P<0.0001). On day 42, there was less cardiac hypertrophy and inflammation in IRF-9 −/− mice compared to WT controls (p<0.05). There was no difference in fibrosis. The mature T-lymphocyte population, defined as CD4 or CD8 single positive, was statistically identical in the two populations up until and including day 28 post-infection. However on day 42 there was a dramatic increase in the number of cytotoxic and helper T-Cells in the wild-type mice that was not observed in the IRF-9 −/− spleens (p<0.05). CONCLUSIONS: These data suggest a novel dual role of IRF-9 in not only regulating interferon in acute stage of viral infection in myocarditis, but also late acquired immunity activation, including CD4/8 populations, contributing to the development of chronic cardiomyopathy.

Wild-type rabies virus phosphoprotein is associated with viral sensitivity to type I interferon treatment

2013 ◽  
Vol 158 (11) ◽  
pp. 2297-2305 ◽  
Author(s):  
Xuefeng Niu ◽  
Lijun Tang ◽  
Tesfai Tseggai ◽  
Yi Guo ◽  
Zhen F. Fu
Keyword(s):  
Rabies Virus ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Treatment ◽  
Wild Type

scholarly journals Peste des Petits Ruminants Virus Nucleocapsid Protein Inhibits Beta Interferon Production by Interacting with IRF3 To Block Its Activation

2019 ◽  
Vol 93 (16) ◽  
Author(s):  
Zixiang Zhu ◽  
Pengfei Li ◽  
Fan Yang ◽  
Weijun Cao ◽  
Xiangle Zhang ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Type I Interferon ◽  
Interferon Regulatory Factor ◽  
Type I ◽  
Peste Des Petits Ruminants ◽  
Type I Ifn ◽  
Regulatory Factor ◽  
N Protein ◽  
Beta Interferon ◽  
Natural Hosts

ABSTRACTPeste des petits ruminants virus (PPRV) is the etiological agent of peste des petits ruminants, causing acute immunosuppression in its natural hosts. However, the molecular mechanisms by which PPRV antagonizes the host immune responses have not been fully characterized. In particular, how PPRV suppresses the activation of the host RIG-I-like receptor (RLR) pathway has yet to be clarified. In this study, we demonstrated that PPRV infection significantly suppresses RLR pathway activation and type I interferon (IFN) production and identified PPRV N protein as an extremely important antagonistic viral factor that suppresses beta interferon (IFN-β) and IFN-stimulated gene (ISG) expression. A detailed analysis showed that PPRV N protein inhibited type I IFN production by targeting interferon regulatory factor 3 (IRF3), a key molecule in the RLR pathway required for type I IFN induction. PPRV N protein interacted with IRF3 (but not with other components of the RLR pathway, including MDA5, RIG-I, VISA, TBK1, and MITA) and abrogated the phosphorylation of IRF3. As expected, PPRV N protein also considerably impaired the nuclear translocation of IRF3. The TBK1-IRF3 interaction was involved significantly in IRF3 phosphorylation, and we showed that PPRV N protein inhibits the association between TBK1 and IRF3, which in turn inhibits IRF3 phosphorylation. The amino acid region 106 to 210 of PPRV N protein was determined to be essential for suppressing the nuclear translocation of IRF3 and IFN-β production, and the 140 to 400 region of IRF3 was identified as the crucial region for the N-IRF3 interaction. Together, our findings demonstrate a new mechanism evolved by PPRV to inhibit type I IFN production and provide structural insights into the immunosuppression caused by PPRV.IMPORTANCEPeste des petits ruminants is a highly contagious animal disease affecting small ruminants, which threatens both small livestock and endangered susceptible wildlife populations in many countries. The causative agent, peste des petits ruminants virus (PPRV), often causes acute immunosuppression in its natural hosts during infection. Here, for the first time, we demonstrate that N protein, the most abundant protein of PPRV, plays an extremely important role in suppression of interferon regulatory factor 3 (IRF3) function and type I interferon (IFN) production by interfering with the formation of the TBK1-IRF3 complex. This study explored a novel antagonistic mechanism of PPRV.

scholarly journals Inactivation of the type I interferon pathway reveals long double‐stranded RNA ‐mediated RNA interference in mammalian cells

2016 ◽  
Vol 35 (23) ◽  
pp. 2505-2518 ◽  
Author(s):  
Pierre V Maillard ◽  
Annemarthe G Van der Veen ◽  
Safia Deddouche‐Grass ◽  
Neil C Rogers ◽  
Andres Merits ◽  
...  
Keyword(s):  
Rna Interference ◽  
Mammalian Cells ◽  
Type I Interferon ◽  
Type I ◽  
Double Stranded Rna ◽  
Interferon Pathway
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