Expression of latent and replicative-infection genes of Epstein-Barr virus in macrophage

Shimakage, Misuzu; Kimura, Michio; Yanoma, Shunsuke; Ibe, Masahiro; Yokota, Shumpei; Tsujino, G; Kozuka, Takehito; Dezawa, Torn; Tamura, Shinji; Ohshima, Atsushi; Yutsudo, Masuo; Hakura, Akira

doi:10.1007/s007050050492

Cited by 34 publications

(32 citation statements)

References 19 publications

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“…Taken together, we can postulate that targeting monocytes/macrophages may represent an evolutionary advantage for ensuring propagation and persistence of EBV and other herpesviruses within the host (8,30,33,36). This was reinforced by another study which presented evidence of EBV replication in macrophages (44). Cultured macrophages obtained from patients with benign or malignant neoplasms and from healthy donors were kept in culture for several weeks.…”

Section: Discussionmentioning

confidence: 96%

Infection of Primary Human Monocytes by Epstein-Barr Virus

Savard

Bélanger

Tardif

et al. 2000

J Virol

115

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Previous studies have reported that infection of monocytes by viruses such as cytomegalovirus and human immunodeficiency virus weakens host natural immunity. In the present study, we demonstrated the capability of Epstein-Barr virus (EBV) to infect and replicate in freshly isolated human monocytes. Using electron microscopy analysis, we observed the presence of EBV virions in the cytoplasm and nuclei of approximately 20% of monocytes. This was confirmed by Southern blot analysis of EBV genomic DNA sequences in isolated nuclei from monocytes. Infection of monocytes by EBV leads to the activation of the replicative cycle. This was supported by the detection of immediate-early lytic mRNA BZLF-1 transcripts, and by the presence of two early lytic transcripts (BALF-2, which appears to function in DNA replication, and BHRF-1, also associated with the replicative cycle). The late lytic BcLF-1 transcripts, which code for the major nucleocapsid protein, were also detected, as well as EBNA-1 transcripts. However, attempts to detect EBNA-2 transcripts have yielded negative results. Viral replication was also confirmed by the release of newly synthesized infectious viral particles in supernatants of EBV-infected monocytes. EBV-infected monocytes were found to have significantly reduced phagocytic activity, as evaluated by the quantification of ingested carboxylated fluoresceinated latex beads. Taken together, our results suggest that EBV infection of monocytes and alteration of their biological functions might represent a new mechanism to disrupt the immune response and promote viral propagation during the early stages of infection. Epstein-Barr virus (EBV), a member of theHerpesviridae family, has long demonstrated its capabilities to adapt and evade host defense mechanisms. While it was mainly believed that EBV infects only B cells and epithelial cells of the oropharynx, there is growing evidence that EBV targeted cells are broader than initially believed. In fact, recent studies have demonstrated that EBV can infect thymocytes, as revealed by the detection of BZLF-1 and EBV nuclear antigen (EBNA)-1

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Section: Discussionmentioning

confidence: 96%

Infection of Primary Human Monocytes by Epstein-Barr Virus

Savard

Bélanger

Tardif

et al. 2000

J Virol

115

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“…It is well established that EBV can productively infect monocytes and macrophages and that following infection there are changes in the expression of various cytokines/chemokines (22)(23)(24)48). It has been suggested that EBV induces the production of cytokines/chemokines in monocytes/macrophages by at least two distinct mechanisms (11,23), the first one is through the interaction of EBV envelope glycoproteins, such as gp350, with cellular receptors, and the second mechanism requires virus replication.…”

Section: Discussionmentioning

confidence: 99%

The EBV-Encoded dUTPase Activates NF-κB through the TLR2 and MyD88-Dependent Signaling Pathway

Ariza

Glaser

Kaumaya

et al. 2009

The Journal of Immunology

134

159

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The innate immune response plays a key role as the primary host defense against invading pathogens including viruses. We have previously shown that treatment of human monocyte-derived macrophages with EBV-encoded dUTPase induces the expression of proinflammatory cytokines through the activation of NF-κB. However, the receptor responsible for EBV-encoded dUTPase-mediated biological effects is not known. In this study, we demonstrate that the purified EBV-encoded dUTPase activates NF-κB in a dose-dependent manner through TLR2 and requires the recruitment of the adaptor molecule MyD88 but not CD14. Furthermore, activation of NF-κB was abrogated by anti-TLR2, anti-EBV-encoded dUTPase blocking Abs and the overexpression of a dominant negative construct of MyD88 in human embryonic kidney 293 cells expressing TLR2. In addition, treatment of human monocyte-derived macrophages with the anti-EBV-encoded dUTPase Ab 7D6 or the anti-TLR2 Ab blocked the production of IL-6 by the EBV-encoded dUTPase. To our knowledge, this is the first report demonstrating that a nonstructural protein encoded by EBV is a pathogen-associated molecular pattern and that it has immunomodulatory functions. Although additional studies are necessary to define the signaling pathways activated by the EBV-encoded dUTPase and to determine its role in modulating immune responses to EBV infection, our results suggest that the dUTPase could be a potential target for the development of novel therapeutic agents against infections caused by EBV.

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“…After primary infection, EBV establishes latency to ensure its life-long persistence in the host. Although the major target cells for EBV infection are B lymphocytes, many other cell types have been reported to be permissive of EBV (1)(2)(3)(4)(5). Because EBV has the potential to modulate the immune system by altering several cellular functions (6), a rapid detection of the virus is therefore essential to limit the spread of infection and to control the outgrowth of latently infected B cells.…”

mentioning

confidence: 99%

TLR9 Contributes to the Recognition of EBV by Primary Monocytes and Plasmacytoid Dendritic Cells

Fiola

Gosselin

Takada

et al. 2010

The Journal of Immunology

137

136

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TLR9 plays an important role in innate defense against viruses by the detection of CpG motifs of foreign DNA within intracellular compartments. In this study, we evaluated the ability of EBV to promote monocyte and plasmacytoid dendritic cell (pDC) activation and cytokine release through TLR9 activation. We demonstrated that treatment of primary monocytes with EBV and with purified EBV DNA induced the release of IL-8 through TLR9. Activation of TLR9 by viral DNA requires endosomal maturation because pretreatment of monocytes with chloroquine strongly reduced IL-8 secretion. However, pretreatment of monocytes with siRNA directed against TLR2, with inhibitory ODN (iODN) or with a combination of both inhibitors strongly reduced the secretion of IL-8, providing evidence of a dual action of TLR2 and TLR9 in EBV recognition by monocytes. In contrast, production of MCP-1 and IL-10 in EBV-treated monocytes was mainly regulated through TLR2. Although EBV does not establish infection in pDCs, challenge with either live EBV particles or isolated EBV DNA was found to induce the release of IFN-α through TLR9, as supported by blockage of TLR9 activity with iODN or chloroquine. The role of TLR9 in the recognition of EBV by pDCs appears to be dominant, as confirmed by the marked inhibitory effect of iODN observed on the synthesis of IFN-α, IL-6, and IL-8 by pDCs. These results demonstrate that recognition of EBV by TLR9 is differently orchestrated in primary monocytes and pDCs to optimize viral recognition and antiviral response.

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Expression of latent and replicative-infection genes of Epstein-Barr virus in macrophage

Cited by 34 publications

References 19 publications

Infection of Primary Human Monocytes by Epstein-Barr Virus

Infection of Primary Human Monocytes by Epstein-Barr Virus

The EBV-Encoded dUTPase Activates NF-κB through the TLR2 and MyD88-Dependent Signaling Pathway

TLR9 Contributes to the Recognition of EBV by Primary Monocytes and Plasmacytoid Dendritic Cells

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