Coordinate Regulation of DNA Damage and Type I Interferon Responses Imposes an Antiviral State That Attenuates Mouse Gammaherpesvirus Type 68 Replication in Primary Macrophages

Mboko, Wadzanai P.; Mounce, Bryan C.; Wood, Brian D.; Kulinski, Joseph M.; Corbett, John A.; Tarakanova, Vera L.

doi:10.1128/jvi.07119-11

Cited by 26 publications

(30 citation statements)

References 66 publications

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“…We and others have recently shown that the physiological DDR leads to induction of antiviral type I IFN responses (6,32), adding another important factor to the gammaherpesvirus-DDR equation. Because type I IFN suppresses MHV68 replication and reactivation in vivo (3,20) and due to virus-driven activation of the DDR in infected cells (42), it is not surprising that MHV68 uncouples the DDR-type I IFN connection in the context of lytic infection of primary macrophages (32).…”

Section: Implications For A-t and Other Ddr-linked Diseasesmentioning

confidence: 99%

“…Because type I IFN suppresses MHV68 replication and reactivation in vivo (3,20) and due to virus-driven activation of the DDR in infected cells (42), it is not surprising that MHV68 uncouples the DDR-type I IFN connection in the context of lytic infection of primary macrophages (32). Because virus-driven DDR induction is not limited to the MHV68 system, in the future it will be important to define the mechanism by which MHV68 interferes with type I IFN responses induced upon activation of the DDR.…”

Section: Implications For A-t and Other Ddr-linked Diseasesmentioning

confidence: 99%

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Ataxia Telangiectasia Mutated Kinase Controls Chronic Gammaherpesvirus Infection

Kulinski

Leonardo

Mounce

et al. 2012

J Virol

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Gammaherpesviruses, such as Epstein-Barr virus (EBV), are ubiquitous cancer-associated pathogens that interact with DNA damage response, a tumor suppressor network. Chronic gammaherpesvirus infection and pathogenesis in a DNA damage response-insufficient host are poorly understood. Ataxia-telangiectasia (A-T) is associated with insufficiency of ataxia-telangiectasia mutated (ATM), a critical DNA damage response kinase. A-T patients display a pattern of anti-EBV antibodies suggestive of poorly controlled EBV replication; however, parameters of chronic EBV infection and pathogenesis in the A-T population remain unclear. Here we demonstrate that chronic gammaherpesvirus infection is poorly controlled in an animal model of A-T. Intriguingly, in spite of a global increase in T cell activation and numbers in wild-type (wt) and ATM-deficient mice in response to mouse gammaherpesvirus 68 (MHV68) infection, the generation of an MHV68-specific immune response was altered in the absence of ATM. Our finding that ATM expression is necessary for an optimal adaptive immune response against gammaherpesvirus unveils an important connection between DNA damage response and immune control of chronic gammaherpesvirus infection, a connection that is likely to impact viral pathogenesis in an ATM-insufficient host.

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Section: Implications For A-t and Other Ddr-linked Diseasesmentioning

confidence: 99%

Section: Implications For A-t and Other Ddr-linked Diseasesmentioning

confidence: 99%

Ataxia Telangiectasia Mutated Kinase Controls Chronic Gammaherpesvirus Infection

Kulinski

Leonardo

Mounce

et al. 2012

J Virol

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“…mRNA measurement. Total RNA was harvested from cells, DNase treated, and reverse transcribed as previously described (29). cDNA was assessed in triplicate, along with corresponding negative reverse transcription (RT) reactions, by real-time PCR using an iCycler (Bio-Rad, Hercules, CA) (29,30).…”

Section: Animals and Primary Cell Cultures C57bl/6j (Bl6) Irf-1mentioning

confidence: 99%

“…Cell lysates were collected and analyzed as previously described (29,30). The antibodies used were anti-␤-actin (1:20,000; Novus Biological, Littleton, CO), anti-total Stat1 (1:3,000; Santa Cruz Biotechnology, Santa Cruz, CA), anti-IRF-1 (1:1,000; Cell Signaling Technology, Danvers, MA), anti-ssDBP (1:1,000 [30]), anti-ISG15 (1:4,000; a gift of Debbie Lenschow), and a secondary goat antimouse or antirabbit horseradish peroxidase-conjugated secondary antibody (1:25,000; Jackson ImmunoResearch, West Grove, PA).…”

Section: Animals and Primary Cell Cultures C57bl/6j (Bl6) Irf-1mentioning

confidence: 99%

“…The relative abundance of each cDNA was normalized to the corresponding GAPDH levels using the ⌬C T threshold cycle (C T ) method. Primers for the MHV68 DNA synthesis genes, IRF-1, universal alpha IFN (IFN-␣), IFN-␤, GAPDH (29,31,32), and CH25H (26) were described previously. The primers used to measure the levels of mRNA for MHV68-targeting antiviral genes are listed in Table 1.…”

Section: Animals and Primary Cell Cultures C57bl/6j (Bl6) Irf-1mentioning

confidence: 99%

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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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Viral and Cellular Genomes Activate Distinct DNA Damage Responses

Shah

O’Shea

2015

Cell

101

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Summary In response to cellular genome breaks, MRE11/RAD50/NBS1 (MRN) activates a global ATM DNA damage response (DDR) that prevents cellular replication. Here we show that MRN-ATM also has critical functions in defending the cell against DNA viruses. We reveal temporally distinct responses to adenovirus genomes: a critical MRN-ATM DDR that must be inactivated by E1B-55K/E4-ORF3 viral oncoproteins and a global MRN independent ATM DDR to viral nuclear domains that does not impact viral replication. We show that MRN binds to adenovirus genomes and activates a localized ATM response that specifically prevents viral DNA replication. In contrast to chromosomal breaks, ATM activation is not amplified by H2AX across megabases of chromatin to induce global signaling and replicative arrest. Thus, γH2AX foci discriminate ‘self’ and ‘non-self’ genomes and determine if a localized anti-viral or global ATM response is appropriate. This provides an elegant mechanism to neutralize viral genomes without jeopardizing cellular viability.

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Coordinate Regulation of DNA Damage and Type I Interferon Responses Imposes an Antiviral State That Attenuates Mouse Gammaherpesvirus Type 68 Replication in Primary Macrophages

Cited by 26 publications

References 66 publications

Ataxia Telangiectasia Mutated Kinase Controls Chronic Gammaherpesvirus Infection

Ataxia Telangiectasia Mutated Kinase Controls Chronic Gammaherpesvirus Infection

Interferon Regulatory Factor 1 Restricts Gammaherpesvirus Replication in Primary Immune Cells

Viral and Cellular Genomes Activate Distinct DNA Damage Responses

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