Gammaherpesvirus targets peritoneal B-1 B cells for long-term latency

Rekow, Michaela M.; Darrah, Eric J.; Mboko, Wadzanai P.; Lange, Philip T.; Tarakanova, Vera L.

doi:10.1016/j.virol.2016.02.022

Cited by 28 publications

(32 citation statements)

References 13 publications

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“…MHV68-positive cells were enriched in most peritoneal B cell populations compared to peritoneal non-B cells (Fig. 6B and C), consistent with our observation in BL6 mice (32), suggesting that the genetic background does not have a profound influence on the peritoneal cell types hosting latent MHV68. Interestingly, while the highest frequency of MHV68 DNA-positive cells was found in the B-1b B cells of either B-Cre genotype (Fig.…”

Section: Resultssupporting

confidence: 89%

“…However, the type of B cells harboring MHV68 in the peritoneum was not identified. We have since shown that B-1 B cells predominantly support peritoneal MHV68 latency in BL6 mice, regardless of the route of inoculation (32). In the current study, we show that MHV68 tropism for peritoneal B-1 B cells is also observed in mice on a mixed genetic background, suggesting that infection of B-1 B cells is not unique to the BL6 mouse strain.…”

Section: Discussionsupporting

confidence: 56%

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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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Section: Resultssupporting

confidence: 89%

Section: Discussionsupporting

confidence: 56%

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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“…We have previously reported that ATM facilitates MHV68 replication in primary macrophages (Tarakanova, Leung-Pineda et al, 2007), a physiologically relevant immune cell type (Rekow, Darrah et al, 2016; Weck, Kim et al, 1999). This proviral role of ATM is most obvious under conditions of low multiplicity of infection (MOI) (Fig.…”

Section: Resultsmentioning

confidence: 99%

ATM supports gammaherpesvirus replication by attenuating type I interferon pathway

et al. 2017

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Ataxia-Telangiectasia mutated (ATM) kinase participates in multiple networks, including DNA damage response, oxidative stress, and mitophagy. ATM also supports replication of diverse DNA and RNA viruses. Gammaherpesviruses are prevalent cancer-associated viruses that benefit from ATM expression during replication. This proviral role of ATM had been ascribed to its signaling within the DNA damage response network; other functions of ATM have not been considered. In this study increased type I interferon (IFN) responses were observed in ATM deficient gammaherpesvirus-infected macrophages. Using a mouse model that combines ATM and type I IFN receptor deficiencies we show that increased type I IFN response in the absence of ATM fully accounts for the proviral role of ATM during gammaherpesvirus replication. Further, increased type I IFN response rendered ATM deficient macrophages more susceptible to antiviral effects of type II IFN. This study identifies attenuation of type I IFN responses as the primary mechanism underlying proviral function of ATM during gammaherpesvirus infection.

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“…To address this possibility, mice were infected IP as described above and peritoneal cells were collected at 8 and 16 dpi, stained for β-lactamase, CD19, and CD5. CD19 was used to distinguish between non-B cells and B cells (CD19 + ) and CD5 expression on CD19 + cells was used to identify B1-a cells, which are known to harbor latent virus in the peritoneum (Fig 4A) [13, 28]. We saw no significant difference in the cellular distribution of infection between WT and cycKO viruses (Fig 4B), but a profound decrease in the frequency of LANA::βla + cells in peritoneal cells harvested from cycKO.βla infected mice (Fig 4C).…”

Section: Resultsmentioning

confidence: 99%

“…Numerous studies suggest that a primary source of reactivating virus is plasma cells [14, 18-20]. Other studies indicate that in the peritoneal compartment, infected macrophages and/or B1 B cells are major cell types capable of reactivation [12, 13].…”

Section: Introductionmentioning

confidence: 99%

The gammaherpesvirus 68 viral cyclin facilitates reactivation by promoting latent gene expression

Niemeyer

Gibson

Berger

et al. 2019

Preprint

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Gammaherpesvirus targets peritoneal B-1 B cells for long-term latency

Cited by 28 publications

References 13 publications

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

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

ATM supports gammaherpesvirus replication by attenuating type I interferon pathway

The gammaherpesvirus 68 viral cyclin facilitates reactivation by promoting latent gene expression

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