ATM supports gammaherpesvirus replication by attenuating type I interferon pathway

Darrah, Eric J.; Stoltz, Kyle; Ledwith, Mitchell P.; Tarakanova, Vera L.

doi:10.1016/j.virol.2017.07.014

Cited by 7 publications

(5 citation statements)

References 73 publications

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“…Interestingly, MHV68 infection of primary macrophages failed to alter low levels of endogenous RT activity at both high (Fig. 1A) and low multiplicity of infection (Darrah et al, 2017), in contrast to published HCMV studies.…”

Section: Resultscontrasting

confidence: 71%

Tumor suppressor Interferon Regulatory Factor 1 selectively blocks expression of endogenous retrovirus

et al. 2019

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Endogenous retroviruses (ERVs) comprise 10% of the genome, with many of these transcriptionally silenced post early embryogenesis. Several stimuli, including exogenous virus infection and cellular transformation can reactivate ERV expression via a poorly understood mechanism. We identified Interferon Regulatory Factor 1 (IRF-1), a tumor suppressor and an antiviral host factor, as a suppressor of ERV expression. IRF-1 decreased expression of a specific mouse ERV in vitro and in vivo. IRF-3, but not IRF-7, also decreased expression of distinct ERV families, suggesting that suppression of ERVs is a relevant biological function of the IRF family. Given the emerging appreciation of the physiological relevance of ERV expression in cancer, IRF-1-mediated suppression of specific ERVs may contribute to the overall tumor suppressor activity of this host factor.

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Section: Resultscontrasting

confidence: 71%

Tumor suppressor Interferon Regulatory Factor 1 selectively blocks expression of endogenous retrovirus

et al. 2019

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“…We showed that ataxia telangiectasia mutated (ATM) kinase was required to amplify serine 139 phosphorylation of H2AX by MHV68 orf36 and that ATM expression facilitated replication of wild-type but not orf36-deficient MHV68 in primary macrophages (39). This proviral effect of ATM expression is entirely due to the ability of ATM to attenuate type I IFN signaling and not to its role in the DNA damage response (47). Importantly, germinal center responses were equivalently induced in control and ATM Ϫ/Ϫ mice (data not shown), indicating that activation of ATM by orf36 is not involved in the phenotypes observed in the current study.…”

Section: Discussionmentioning

confidence: 98%

Conserved Gammaherpesvirus Protein Kinase Selectively Promotes Irrelevant B Cell Responses

Darrah

Jondle

Johnson

et al. 2019

J Virol

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Gammaherpesviruses are ubiquitous pathogens that are associated with B cell lymphomas. In the early stages of chronic infection, these viruses infect naive B cells and subsequently usurp the B cell differentiation process through the germinal center response to ensure latent infection of long-lived memory B cells. A unique feature of early gammaherpesvirus chronic infection is a robust differentiation of irrelevant, virus-nonspecific B cells with reactivities against self-antigens and antigens of other species. In contrast, protective, virus-specific humoral responses do not reach peak levels until a much later time. While several host factors are known to either promote or selectively restrict gammaherpesvirus-driven germinal center response, viral mechanisms that contribute to the irrelevant B cell response have not been defined. In this report we show that the expression and the enzymatic activity of the gammaherpesvirus-encoded conserved protein kinase selectively facilitates the irrelevant, but not virus-specific, B cell responses. Further, we show that lack of interleukin-1 (IL-1) receptor attenuates gammaherpesvirus-driven B cell differentiation and viral reactivation. Because germinal center B cells are thought to be the target of malignant transformation during gammaherpesvirus-driven lymphomagenesis, identification of host and viral factors that promote germinal center responses during gammaherpesvirus infection may offer an insight into the mechanism of gammaherpesvirus pathogenesis. IMPORTANCE Gammaherpesviruses are ubiquitous cancer-associated pathogens that usurp the B cell differentiation process to establish life-long latent infection in memory B cells. A unique feature of early gammaherpesvirus infection is the robust increase in differentiation of B cells that are not specific for viral antigens and instead encode antibodies that react with self-antigens and antigens of other species. Viral mechanisms that are involved in driving such irrelevant B cell differentiation are not known. Here, we show that gammaherpesvirus-encoded conserved protein kinase and host IL-1 signaling promote irrelevant B cell responses and gammaherpesvirusdriven germinal center responses, with the latter thought to be the target of viral transformation.

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“…However, the mechanism remains unclear. We have recently found that ATM attenuates type I interferon (IFN) responses during MHV68 replication in primary macrophages, and it is this attenuation that fully accounts for the proviral activity of ATM during gammaherpesvirus replication in vitro (44). It is tempting to speculate that the infected-cell-intrinsic expression of ATM and subsequent attenuation of the type I IFN response also promote virus reactivation during chronic infection, a hypothesis that is being tested in ongoing studies.…”

Section: Discussionmentioning

confidence: 99%

B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection

Darrah

Kulinski

Mboko

et al. 2017

J Virol

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Manipulation of host cellular pathways is a strategy employed by gammaherpesviruses, including mouse gammaherpesvirus 68 (MHV68), in order to negotiate a chronic infection. Ataxia-telangiectasia mutated (ATM) plays a unique yet incompletely understood role in gammaherpesvirus infection, as it has both proviral and antiviral effects. Chronic gammaherpesvirus infection is poorly controlled in a host with global ATM insufficiency, whether the host is a mouse or a human. In contrast, ATM facilitates replication, reactivation, and latency establishment of several gammaherpesviruses in vitro, suggesting that ATM is proviral in the context of infected cell cultures. The proviral role of ATM is also evident in vivo, as myeloidspecific ATM expression facilitates MHV68 reactivation during the establishment of viral latency. In order to better understand the complex relationship between host ATM and gammaherpesvirus infection, we depleted ATM specifically in B cells, a cell type critical for chronic gammaherpesvirus infection. B cell-specific ATM deficiency attenuated the establishment of viral latency due to compromised differentiation of ATM-deficient B cells. Further, we found that during long-term infection, peritoneal B-1b, but not related B-1a, B cells display the highest frequency of gammaherpesvirus infection. While ATM expression did not affect gammaherpesvirus tropism for B-1 B cells, B cell-specific ATM expression was necessary to support viral reactivation from peritoneal cells during long-term infection. Thus, our study reveals a role of ATM as a host factor that promotes chronic gammaherpesvirus infection of B cells.IMPORTANCE Gammaherpesviruses infect a majority of the human population and are associated with cancer, including B cell lymphomas. ATM is a unique host kinase that has both proviral and antiviral roles in the context of gammaherpesvirus infection. Further, there is insufficient understanding of the interplay of these roles in vivo during chronic infection. In this study, we show that ATM expression by splenic B cells is required for efficient establishment of gammaherpesvirus latency. We also show that ATM expression by peritoneal B cells is required to facilitate viral reactivation during long-term infection. Thus, our study defines a proviral role of B cellspecific ATM expression during chronic gammaherpesvirus infection.KEYWORDS ATM, gammaherpesvirus, B cell, T cell response, reactivation, chronic infection A taxia-telangiectasia (A-T) mutated (ATM) kinase is a multifunctional kinase, insufficiency of which in humans manifests as A-T (1, 2). The function of ATM was originally defined in the context of response to double-stranded DNA breaks. However,

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ATM supports gammaherpesvirus replication by attenuating type I interferon pathway

Cited by 7 publications

References 73 publications

Tumor suppressor Interferon Regulatory Factor 1 selectively blocks expression of endogenous retrovirus

Tumor suppressor Interferon Regulatory Factor 1 selectively blocks expression of endogenous retrovirus

Conserved Gammaherpesvirus Protein Kinase Selectively Promotes Irrelevant B Cell Responses

B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection

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