Gamma Interferon-Induced Interferon Regulatory Factor 1-Dependent Antiviral Response Inhibits Vaccinia Virus Replication in Mouse but Not Human Fibroblasts

Trilling, Mirko; Le, Vu Thuy Khanh; Zimmermann, Albert; Ludwig, Holger; Pfeffer, Klaus; Sutter, Gerd; Smith, Geoffrey L.; Hengel, Hartmut

doi:10.1128/jvi.02042-08

Cited by 40 publications

(42 citation statements)

References 81 publications

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“…Interestingly, IRF-1 expression was required for IFN-␥-mediated suppression of mouse norovirus (MNV) replication in primary macrophages in vitro (53). A similar phenotype was seen with vaccinia virus (VACV), where IRF-1 was required for IFN-␥-mediated suppression of VACV replication in mouse fibroblasts (54). Because IFN-␥ is not expressed in primary macrophages infected with MHV68 in vitro (our unpublished observations), it is possible that IRF-1 has additional, type I IFN-independent functions that attenuate MHV68 infection, especially in vivo where IFN-␥ is present (55).…”

Section: Discussionmentioning

confidence: 67%

Interferon Regulatory Factor 1 Restricts Gammaherpesvirus Replication in Primary Immune Cells

Mboko

Mounce

Emmer

et al. 2014

J Virol

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Gammaherpesviruses are ubiquitous pathogens that establish a lifelong infection and are associated with cancer. In spite of the high seroprevalence of infection, the risk factors that predispose the host toward gammaherpesvirus-induced malignancies are still poorly understood. Interferon (IFN) regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. On the basis of its biology, IRF-1 represents a plausible host factor to attenuate gammaherpesvirus infection and tumorigenesis. In this study, we show that IRF-1 restricts gammaherpesvirus replication in primary macrophages, a physiologically relevant immune cell type. In spite of the known role of IRF-1 in stimulating type I IFN expression, induction of a global type I IFN response was similar in IRF-1-deficient and -proficient macrophages during gammaherpesvirus infection. However, IRF-1 was required for optimal expression of cholesterol-25-hydroxylase, a host enzyme that restricted gammaherpesvirus replication in primary macrophages and contributed to the antiviral effects of IRF-1. In summary, the current study provides an insight into the mechanism by which IRF-1 attenuates gammaherpesvirus replication in primary immune cells, a mechanism that is likely to contribute to the antiviral effects of IRF-1 in other virus systems. IMPORTANCEInterferon regulatory factor 1 (IRF-1) is a transcription factor that regulates innate and adaptive immune responses and functions as a tumor suppressor. IRF-1 restricts the replication of diverse viruses; however, the mechanisms responsible for the antiviral effects of IRF-1 are still poorly understood. Gammaherpesviruses are ubiquitous pathogens that are associated with the induction of several malignancies. Here we show that IRF-1 expression attenuates gammaherpesvirus replication in primary macrophages, in part by increasing expression of cholesterol-25-hydroxylase (CH25H). CH25H and its product, 25-hydroxycholesterol, restrict replication of diverse virus families. Thus, our findings offer an insight into the mechanism by which IRF-1 attenuates the replication of gammaherpesviruses, a mechanism that is likely to be applicable to other virus systems.

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Section: Discussionmentioning

confidence: 67%

Interferon Regulatory Factor 1 Restricts Gammaherpesvirus Replication in Primary Immune Cells

Mboko

Mounce

Emmer

et al. 2014

J Virol

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“…As human IFN␥ does not signal in mouse or rat cells, evidence that microinjection of human IFN␥ elicited antiviral activity in murine cells suggested that the IFNGR provides species specific responses to IFN␥ (31). Further evidence showing that retention of IFN␥ within cells also resulted in an IFN␥-dependent signaling leaded researchers to further claim that the IFNGR drives species specificity responses (32,33).…”

Section: Alternative Mechanisms Regulating the Ifn␥ Signaling Via Endmentioning

confidence: 99%

Current prospects of type II interferon γ signaling and autoimmunity

Green

Young

Valencia

2017

Journal of Biological Chemistry

139

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Edited by Charles E. SamuelInterferon ␥ (IFN␥) is a pleiotropic protein secreted by immune cells. IFN␥ signals through the IFN␥ receptor, a protein complex that mediates downstream signaling events. Studies into IFN␥ signaling have provided insight into the general concepts of receptor signaling, receptor internalization, regulation of distinct signaling pathways, and transcriptional regulation. Although IFN␥ is the central mediator of the adaptive immune response to pathogens, it has been shown to be involved in several non-infectious physiological processes. This review will provide an introduction into IFN␥ signaling biology and the functional roles of IFN␥ in the autoimmune response.According to the National Institutes of Health, autoimmune diseases (ADs) 3 are one of the top 10 leading causes of death in female children and women in all age groups up to 64 years of age (1). Excess secretion of IFNs has been associated with development of human ADs (2). Interferons (IFNs) comprise a family of proteins classified as type I (IFN-␣, -␤, -⑀, -, and -), type II (IFN-␥, herein IFN␥), and type III (IFN-1-4) that have pleiotropic roles in immunity, cancer biology, and autoimmunity (2). Here, we aim to provide a basic understanding of the functions of the type II IFN␥ and the IFN␥-signaling pathway (hereafter referred to as IFN signaling) in a contextual and timing perspective related to the autoimmune environment and the development of ADs.

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“…For immunoblotting, cells were lysed (66) and equal amounts of protein were subjected to SDS-PAGE and transferred to nitrocellulose membranes. Immunoblot analysis was performed using mouse monoclonal antibody (MAb) anti-␤-actin (Sigma), mouse MAb recognizing HCMV pUL83/ pp65 (3A12; AbCam), rabbit polyclonal anti-IB␣ (sc-371; Santa Cruz), rabbit MAb anti-phospho-IB␣ (2859; Cell Signaling), rabbit MAb anti-TNFR1 (3736; Cell Signaling), rabbit polyclonal anti-Fas (sc-1023; Santa Cruz), and rabbit polyclonal anti-HA (Sigma).…”

Section: Methodsmentioning

confidence: 99%

The Cytomegaloviral Protein pUL138 Acts as Potentiator of Tumor Necrosis Factor (TNF) Receptor 1 Surface Density To Enhance ULb′-Encoded Modulation of TNF-α Signaling

Trilling

Hengel

2011

J Virol

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Human cytomegalovirus is a ubiquitous herpesvirus that establishes lifelong latent infection. Changes in immune homeostasis induce the reactivation of lytic infection, which is mostly inapparent in healthy individuals but often causes overt disease in immunocompromised hosts. Based on discrepant tumor necrosis factor receptor 1 surface disposition between human cytomegalovirus AD169 variants differing in the ULb region, we identified the latency-associated gene product pUL138, which also is expressed during productive infection, as a selective potentiator of tumor necrosis factor receptor 1, one of the key receptors of innate immunity. Ectopically expressed pUL138 coprecipitated with tumor necrosis factor receptor 1, extended the protein half-life, and enhanced its signaling responses, thus leading to tumor necrosis factor receptor 1 hyperresponsiveness. Conversely, the targeted deletion of UL138 from the human cytomegaloviral genome strongly reduced tumor necrosis factor receptor 1 surface densities of infected cells. Remarkably, the comparison of UL138 deficiency to ULb deficiency revealed the presence of further positive modulators of tumor necrosis factor alpha signal transduction encoded within the human cytomegalovirus ULb region, identifying this region as a hub for multilayered tumor necrosis factor alpha signaling regulation.

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Gamma Interferon-Induced Interferon Regulatory Factor 1-Dependent Antiviral Response Inhibits Vaccinia Virus Replication in Mouse but Not Human Fibroblasts

Cited by 40 publications

References 81 publications

Interferon Regulatory Factor 1 Restricts Gammaherpesvirus Replication in Primary Immune Cells

Interferon Regulatory Factor 1 Restricts Gammaherpesvirus Replication in Primary Immune Cells

Current prospects of type II interferon γ signaling and autoimmunity

The Cytomegaloviral Protein pUL138 Acts as Potentiator of Tumor Necrosis Factor (TNF) Receptor 1 Surface Density To Enhance ULb′-Encoded Modulation of TNF-α Signaling

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