B-cell polyclonal activation and Epstein-Barr viral abortive lytic cycle are two key features in acute infectious mononucleosis

Tabaa, Yassine Al; Tuaillon, Édouard; Jeziorski, Éric; Ouedraogo, David Eric; Bolloré, Karine; Rubbo, Pierre-Alain; Foulongne, Vincent; Rodière, M.; Vendrell, Jean-Pierre

doi:10.1016/j.jcv.2011.05.023

Cited by 25 publications

(27 citation statements)

References 20 publications

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“…EBV lytic replication is known to occur in the oropharyngeal compartment during IM. However, the existence of lytically infected B cells in peripheral blood has been questioned (34)(35)(36). In contrast to our findings, a previous study was unable to detect lytic replication in peripheral B cells (36).…”

Section: Discussioncontrasting

confidence: 99%

Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes

Hill

Koganti

Zhi

et al. 2013

J Virol

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g Lytic activation of Epstein-Barr virus (EBV) is central to its life cycle and to most EBV-related diseases. However, not every EBVinfected B cell is susceptible to lytic activation. This lack of uniform susceptibility to lytic activation also directly impacts the success of viral oncolytic therapy for EBV cancers, yet determinants of susceptibility to lytic induction signals are not well understood. To determine if host factors influence susceptibility to EBV lytic activation, we developed a technique to separate lytic from refractory cells and reported that EBV lytic activation occurs preferentially in cells with lower levels of signal transducer and activator of transcription 3 (STAT3). Using this tool to detect single cells, we now extend the correlation between STAT3 and lytic versus refractory states to EBV-infected circulating B cells in patients with primary EBV infection, leading us to investigate whether STAT3 controls susceptibility to EBV lytic activation. In loss-of-function and gain-of-function studies in EBV-positive B lymphoma and lymphoblastoid cells, we found that the levels of functional STAT3 regulate susceptibility to EBV lytic activation. This prompted us to identify a pool of candidate cellular genes that might be regulated by STAT3 to limit EBV lytic activation. From this pool, we confirmed increases in transcript levels in refractory cells of a set of genes known to participate in transcription repression. Taken together, our findings place STAT3 at a critical crossroads between EBV latency and lytic activation, processes fundamental to EBV lymphomagenesis. E pstein-Barr virus (EBV) infects most humans and persists silently in B lymphocytes. Primary infection with EBV can cause infectious mononucleosis (IM). Under certain circumstances, EBV can cause B-cell lymphomas and epithelial cell cancers (1). Several studies suggest that EBV lytic activation is an important step in the pathogenesis of such EBV-related diseases (2-5). From a therapeutic standpoint, efforts to eliminate EBV-positive tumors using nucleoside analogues after induction of viral lytic activation have shown promise (6-8). However, EBV-infected tumor cells are not fully permissive to lytic induction, as only a fraction of EBV-infected B cells exposed to lytic cycle-inducing agents enters the lytic cycle; the remainder of the population is refractory to lytic induction (9, 10). These refractory cells are not susceptible to oncolytic therapy, necessitating further investigations into the physiology underlying both lytic and refractory states.A general problem with investigating EBV lytic activation is that a mixed population of refractory and lytic cells results from exposure to lytic cycle-inducing stimuli. We therefore developed a technique to separate lytic cells from refractory cells in a mixed population of EBV-infected B cells (9). Our previous studies using this technique showed that host cell determinants regulate susceptibility of EBV-infected B cells to lytic cycle-inducing stimuli (9, 11) and that higher levels o...

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Section: Discussioncontrasting

confidence: 99%

Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes

Hill

Koganti

Zhi

et al. 2013

J Virol

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“…However, there is accumulating evidence, especially in the case of the gamma herpesviruses (Laichalk and Thorley-Lawson, 2005; Al Tabaa et al, 2009, 2011; Myoung and Ganem, 2011; Scholz et al, 2013; Strong et al, 2013), supporting the premise that “ in vivo abortive-lytic replication” is the predominant type of replication occurring in infected cells, which results in the production of immediate early and early proteins, but limited production of new virions. In addition, it has been demonstrated that abortive replication of human immunodeficiency virus (HIV-1) induces pyroptosis (Doitsh et al, 2014; Monroe et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Human herpesviruses-encoded dUTPases: a family of proteins that modulate dendritic cell function and innate immunity

2014

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We have previously shown that Epstein-Barr virus (EBV)-encoded dUTPase can modulate innate immune responses through the activation of TLR2 and NF-κB signaling. However, whether this novel immune function of the dUTPase is specific for EBV or a common property of the Herpesviridae family is not known. In this study, we demonstrate that the purified viral dUTPases encoded by herpes simplex virus type 2 (HSV-2), human herpesvirus-6A (HHV-6A), human herpesvirus-8 (HHV-8) and varicella-zoster virus (VZV) differentially activate NF-κB through ligation of TLR2/TLR1 heterodimers. Furthermore, activation of NF-κB by the viral dUTPases was inhibited by anti-TLR2 blocking antibodies (Abs) and the over-expression of dominant-negative constructs of TLR2, lacking the TIR domain, and MyD88 in human embryonic kidney 293 cells expressing TLR2/TLR1. In addition, treatment of human dendritic cells and PBMCs with the herpesviruses-encoded dUTPases from HSV-2, HHV-6A, HHV-8, and VZV resulted in the secretion of the inflammatory cytokines IL-1β, IL-6, IL-8, IL-12, TNF-α, IL-10, and IFN-γ. Interestingly, blocking experiments revealed that the anti-TLR2 Ab significantly reduced the secretion of cytokines by the various herpesviruses-encoded dUTPases (p < 0.05). To our knowledge, this is the first report demonstrating that a non-structural protein encoded by herpesviruses HHV-6A, HHV-8, VZV and to a lesser extent HSV-2 is a pathogen-associated molecular pattern. Our results reveal a novel function of the virus-encoded dUTPases, which may be important to the pathophysiology of diseases caused by these viruses. More importantly, this study demonstrates that the immunomodulatory functions of dUTPases are a common property of the Herpesviridae family and thus, the dUTPase could be a potential target for the development of novel therapeutic agents against infections caused by these herpesviruses.

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“…1 T-cell replenishment (OR 5 18.6; 95% CI, 2.02-', P 5 .007, Duration of ART 9 (7-10) 9 (7)(8)(9)(10)(11)(12) .95…”

Section: Resultsmentioning

confidence: 99%

“…Patients' characteristics and treatments are presented in Table 1. EBV DNA in B cell, plasma EBV DNA, and ex vivo EBV-associated B cells were analyzed as previously described 10,11 and are detailed in the supplemental Data (available on the Blood website). This study was conducted in accordance with the Declaration of Helsinki.…”

Section: Patients and Study Designmentioning

confidence: 99%

Pivotal role of HIV and EBV replication in the long-term persistence of monoclonal gammopathy in patients on antiretroviral therapy

Ouedraogo

Makinson²,

Vendrell

et al. 2013

Blood

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Key Points• Immunologic and virologic factors are associated with monoclonal gammopathy persistence in HIV-infected patients.• B lymphocytes activation and EBV replication are key features of monoclonal gammopathy.A high prevalence of monoclonal gammopathy (MG) has been observed in HIV-infected patients. We explored the conditions associated with long-term persistence of serum monoclonal protein (M protein) in HIV-infected patients on antiretroviral therapy (ART

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B-cell polyclonal activation and Epstein-Barr viral abortive lytic cycle are two key features in acute infectious mononucleosis

Cited by 25 publications

References 20 publications

Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes

Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes

Human herpesviruses-encoded dUTPases: a family of proteins that modulate dendritic cell function and innate immunity

Pivotal role of HIV and EBV replication in the long-term persistence of monoclonal gammopathy in patients on antiretroviral therapy

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