scholarly journals Bunyamwera Virus Nonstructural Protein NSs Counteracts Interferon Regulatory Factor 3-Mediated Induction of Early Cell Death

2003 ◽  
Vol 77 (14) ◽  
pp. 7999-8008 ◽  
Author(s):  
Alain Kohl ◽  
Reginald F. Clayton ◽  
Friedemann Weber ◽  
Anne Bridgen ◽  
Richard E. Randall ◽  
...  
Keyword(s):  
Cell Death ◽  
Defense Mechanism ◽  
Nonstructural Protein ◽  
Interferon Regulatory Factor ◽  
Wild Type Virus ◽  
Wild Type ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Viral Spread ◽  
Bunyamwera Virus

ABSTRACT The genome of Bunyamwera virus (BUN; family Bunyaviridae, genus Orthobunyavirus) consists of three segments of negative-sense RNA. The smallest segment, S, encodes two proteins, the nonstructural protein NSs, which is nonessential for viral replication and transcription, and the nucleocapsid protein N. Although a precise role in the replication cycle has yet to be attributed to NSs, it has been shown that NSs inhibits the induction of alpha/beta interferon, suggesting that it plays a part in counteracting the host antiviral defense. A defense mechanism to limit viral spread is programmed cell death by apoptosis. Here we show that a recombinant BUN that does not express NSs (BUNdelNSs) induces apoptotic cell death more rapidly than wild-type virus. Screening for apoptosis pathways revealed that the proapoptotic transcription factor interferon regulatory factor 3 (IRF-3) was activated by both wild-type BUN and BUNdelNSs infection, but only wild-type BUN was able to suppress signaling downstream of IRF-3. Studies with a BUN minireplicon system showed that active replication induced an IRF-3-dependent promoter, which was suppressed by the NSs protein. In a cell line (P2.1) defective in double-stranded RNA signaling due to low levels of IRF-3, induction of apoptosis was similar for wild-type BUN and BUNdelNSs. These data suggest that the BUN NSs protein can delay cell death in the early stages of BUN infection by inhibiting IRF-3-mediated apoptosis.

scholarly journals Interferon Regulatory Factor 3 Attenuates Reovirus Myocarditis and Contributes to Viral Clearance

2010 ◽  
Vol 84 (14) ◽  
pp. 6900-6908 ◽  
Author(s):  
Geoffrey H. Holm ◽  
Andrea J. Pruijssers ◽  
Lianna Li ◽  
Pranav Danthi ◽  
Barbara Sherry ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Virulent Strain ◽  
Survival Rates ◽  
Adaptive Immune Response ◽  
Interferon Regulatory Factor ◽  
Wild Type ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Newborn Mice ◽  
Strain Type

ABSTRACT Apoptosis is a pathological hallmark of encephalitis and myocarditis caused by reovirus in newborn mice. In cell culture models, the antiviral transcription factor interferon regulatory factor 3 (IRF-3) enhances reovirus-induced apoptosis following activation via retinoic acid inducible gene I and interferon promoter-stimulating factor 1. To determine the role of IRF-3 in reovirus disease, we infected newborn IRF-3+/+ and IRF-3−/− mice perorally with mildly virulent strain type 1 Lang (T1L) and fully virulent strain type 3 SA+ (T3SA+) and monitored infected animals for survival. Both wild-type and IRF-3−/− mice succumbed with equivalent frequencies to infection with T3SA+. However, the absence of IRF-3 was associated with significantly decreased survival rates following infection with T1L. The two virus strains achieved similar peak titers in IRF-3+/+ and IRF-3−/− mice in the intestine, brain, heart, liver, and spleen. However, by day 12 postinoculation, titers in all organs examined were 10- to 100-fold higher in IRF-3−/− mice than those in wild-type mice. Increased titers were associated with marked pathological changes in all organs examined, especially in the heart, where absence of IRF-3 resulted in severe myocarditis. Cellular and humoral immune responses were equivalent in wild-type and IRF-3−/− animals, suggesting that IRF-3 functions independently of the adaptive immune response to enhance reovirus clearance. Thus, IRF-3 serves to facilitate virus clearance and prevent tissue injury in response to reovirus infection.

scholarly journals Interferon Regulatory Factor 3 Is a Cellular Partner of Rotavirus NSP1

2002 ◽  
Vol 76 (18) ◽  
pp. 9545-9550 ◽  
Author(s):  
Joel W. Graff ◽  
Dana N. Mitzel ◽  
Carla M. Weisend ◽  
Michelle L. Flenniken ◽  
Michele E. Hardy
Keyword(s):  
Nonstructural Protein ◽  
Interferon Regulatory Factor ◽  
Interferon Response ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
C Terminus ◽  
Cellular Partner ◽  
Infected Cells ◽  
Two Hybrid ◽  
Interaction Trap

ABSTRACT The rotavirus nonstructural protein NSP1 is the least conserved protein in the rotavirus genome, and its function in the replication cycle is not known. We employed NSP1 as bait in the yeast two-hybrid interaction trap to identify candidate cellular partners of NSP1 that may provide clues to its function. Interferon regulatory factor 3 (IRF-3) was identified as an NSP1 interactor. NSP1 synthesized in rotavirus-infected cells bound IRF-3 in a glutathione S-transferase pull-down assay, indicating that the interaction was not unique to the two-hybrid system. NSP1 of murine rotavirus strain EW also interacted with IRF-3. NSP1 deletion and point mutants were constructed to map domains important in the interaction between NSP1 and IRF-3. The data suggest that a binding domain resides in the C terminus of NSP1 and that the N-terminal conserved zinc finger is important but not sufficient to mediate binding to IRF-3. We predict that a role for NSP1 in rotavirus-infected cells is to inhibit activation of IRF-3 and diminish the cellular interferon response.

scholarly journals Classical Swine Fever Virus Can Remain Virulent after Specific Elimination of the Interferon Regulatory Factor 3-Degrading Function of Npro

2008 ◽  
Vol 83 (2) ◽  
pp. 817-829 ◽  
Author(s):  
Nicolas Ruggli ◽  
Artur Summerfield ◽  
Ana R. Fiebach ◽  
Laurence Guzylack-Piriou ◽  
Oliver Bauhofer ◽  
...  
Keyword(s):  
Classical Swine Fever Virus ◽  
Nonstructural Protein ◽  
Classical Swine Fever ◽  
Interferon Regulatory Factor ◽  
Fever Virus ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Amino Terminal ◽  
Alpha Beta

ABSTRACT Pestiviruses prevent alpha/beta interferon (IFN-α/β) production by promoting proteasomal degradation of interferon regulatory factor 3 (IRF3) by means of the viral Npro nonstructural protein. Npro is also an autoprotease, and its amino-terminal coding sequence is involved in translation initiation. We previously showed with classical swine fever virus (CSFV) that deletion of the entire Npro gene resulted in attenuation in pigs. In order to elaborate on the role of the Npro-mediated IRF3 degradation in classical swine fever pathogenesis, we searched for minimal amino acid substitutions in Npro that would specifically abrogate this function. Our mutational analyses showed that degradation of IRF3 and autoprotease activity are two independent but structurally overlapping functions of Npro. We describe two mutations in Npro that eliminate Npro-mediated IRF3 degradation without affecting the autoprotease activity. We also show that the conserved standard sequence at these particular positions is essential for Npro to interact with IRF3. Surprisingly, when these two mutations are introduced independently in the backbones of highly and moderately virulent CSFV, the resulting viruses are not attenuated, or are only partially attenuated, in 8- to 10-week-old pigs. This contrasts with the fact that these mutant viruses have lost the capacity to degrade IRF3 and to prevent IFN-α/β induction in porcine cell lines and monocyte-derived dendritic cells. Taken together, these results demonstrate that contrary to previous assumptions and to the case for other viral systems, impairment of IRF3-dependent IFN-α/β induction is not a prerequisite for CSFV virulence.

scholarly journals Role of Interferon Regulatory Factor 3 in Type I Interferon Responses in Rotavirus-Infected Dendritic Cells and Fibroblasts

2007 ◽  
Vol 81 (6) ◽  
pp. 2758-2768 ◽  
Author(s):  
Iyadh Douagi ◽  
Gerald M. McInerney ◽  
Åsa S. Hidmark ◽  
Vassoula Miriallis ◽  
Kari Johansen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nonstructural Protein ◽  
Interferon Regulatory Factor ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Nonstructural Protein 1 ◽  
Subsequent Activation

ABSTRACT The main pathway for the induction of type I interferons (IFN) by viruses is through the recognition of viral RNA by cytosolic receptors and the subsequent activation of interferon regulatory factor 3 (IRF-3), which drives IFN-α/β transcription. In addition to their role in inducing an antiviral state, type I IFN also play a role in modulating adaptive immune responses, in part via their effects on dendritic cells (DCs). Many viruses have evolved mechanisms to interfere with type I IFN induction, and one recently reported strategy for achieving this is by targeting IRF-3 for degradation, as shown for rotavirus nonstructural protein 1 (NSP1). It was therefore of interest to investigate whether rotavirus-exposed DCs would produce type I IFN and/or mature in response to the virus. Our results demonstrate that IRF-3 was rapidly degraded in rotavirus-infected mouse embryonic fibroblasts (MEFs) and type I IFN was not detected in these cultures. In contrast, rotavirus induced type I IFN production in myeloid DCs (mDCs), resulting in their activation. Type I IFN induction in response to rotavirus was reduced in mDCs from IRF-3−/− mice, indicating that IRF-3 was important for mediating the response. Exposure of mDCs to UV-treated rotavirus induced significantly higher type I IFN levels, suggesting that rotavirus-encoded functions also antagonized the response in DCs. However, in contrast to MEFs, this action was not sufficient to completely abrogate type I IFN induction, consistent with a role for DCs as sentinels for virus infection.

scholarly journals Activation of Interferon Regulatory Factor 3 Is Inhibited by the Influenza A Virus NS1 Protein

2000 ◽  
Vol 74 (17) ◽  
pp. 7989-7996 ◽  
Author(s):  
Julie Talon ◽  
Curt M. Horvath ◽  
Rosalind Polley ◽  
Christopher F. Basler ◽  
Thomas Muster ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Binding Protein ◽  
Interferon Regulatory Factor ◽  
Wild Type ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Dsrna Binding ◽  
Dsrna Binding Protein ◽  
Infected Cells

ABSTRACT We present a novel mechanism by which viruses may inhibit the alpha/beta interferon (IFN-α/β) cascade. The double-stranded RNA (dsRNA) binding protein NS1 of influenza virus is shown to prevent the potent antiviral interferon response by inhibiting the activation of interferon regulatory factor 3 (IRF-3), a key regulator of IFN-α/β gene expression. IRF-3 activation and, as a consequence, IFN-β mRNA induction are inhibited in wild-type (PR8) influenza virus-infected cells but not in cells infected with an isogenic virus lacking the NS1 gene (delNS1 virus). Furthermore, NS1 is shown to be a general inhibitor of the interferon signaling pathway. Inhibition of IRF-3 activation can be achieved by the expression of wild-type NS1 intrans, not only in delNS1 virus-infected cells but also in cells infected with a heterologous RNA virus (Newcastle disease virus). We propose that inhibition of IRF-3 activation by a dsRNA binding protein significantly contributes to the virulence of influenza A viruses and possibly to that of other viruses.

scholarly journals Ipr1 Regulation by Cyclic GMP-AMP Synthase/Interferon Regulatory Factor 3 and Modulation of Irgm1 Expression via p53

2020 ◽  
Vol 40 (8) ◽  
Author(s):  
Fayang Liu ◽  
Hongni Xue ◽  
Jie Ke ◽  
Yongyan Wu ◽  
Kezhen Yao ◽  
...  
Keyword(s):  
Cyclic Gmp ◽  
Viral Infections ◽  
Pathogen Resistance ◽  
Interferon Regulatory Factor ◽  
Intracellular Pathogen ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Promoter Characterization ◽  
Ribosomal Protein L11 ◽  
Pathogenic Infection

ABSTRACT Intracellular pathogen resistance 1 (Ipr1) has been found to be a mediator to integrate cyclic GMP-AMP synthase (cGAS)–interferon regulatory factor 3 (IRF3), activated by intracellular pathogens, with the p53 pathway. Previous studies have shown the process of Ipr1 induction by various immune reactions, including intracellular bacterial and viral infections. The present study demonstrated that Ipr1 is regulated by the cGAS-IRF3 pathway during pathogenic infection. IRF3 was found to regulate Ipr1 expression by directly binding the interferon-stimulated response element motif of the Ipr1 promoter. Knockdown of Ipr1 decreased the expression of immunity-related GTPase family M member 1 (Irgm1), which plays critical roles in autophagy initiation. Irgm1 promoter characterization revealed a p53 motif in front of the transcription start site. P53 was found to participate in regulation of Irgm1 expression and IPR1-related effects on P53 stability by affecting interactions between ribosomal protein L11 (RPL11) and transformed mouse 3T3 cell double minute 2 (MDM2). Our results indicate that Ipr1 integrates cGAS-IRF3 with p53-modulated Irgm1 expression.

Interferon regulatory factor 3 in adaptive immune responses

2014 ◽  
Vol 71 (20) ◽  
pp. 3873-3883 ◽  
Author(s):  
Laure Ysebrant de Lendonck ◽  
Valerie Martinet ◽  
Stanislas Goriely
Keyword(s):  
Immune Responses ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Adaptive Immune Responses ◽  
Interferon Regulatory Factor 3 ◽  
Adaptive Immune
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