EBV-encoded dUTPase induces immune dysregulation: Implications for the pathophysiology of EBV-associated disease

Glaser, Ronald; Litsky, Monica L.; Padgett, David A.; Baiocchi, Robert A.; Yang, Eric V.; Chen, Min; Yeh, Peir-En; Green‐Church, Kari B.; Caligiuri, Michael A.; Williams, Marshall V.

doi:10.1016/j.virol.2005.10.034

Cited by 87 publications

(136 citation statements)

References 43 publications

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“…Detailed methods for the purification of the EBV-encoded dUTPase have been previously reported (32,33). All EBV-encoded dUTPase preparations were tested as described previously (32) and were free of detectable levels of LPS, peptidoglycan (SLP-HS), DNA, or RNA.…”

Section: Purification Of the Ebv-encoded Dutpasementioning

confidence: 99%

“…All EBV-encoded dUTPase preparations were tested as described previously (32) and were free of detectable levels of LPS, peptidoglycan (SLP-HS), DNA, or RNA. Protein concentration was determined with a Coomassie Brilliant Blue dye-binding assay (BioRad Laboratories) using BSA as the standard.…”

Section: Purification Of the Ebv-encoded Dutpasementioning

confidence: 99%

“…We have previously demonstrated that the EBV-encoded dUTPase induced the expression of proinflammatory cytokines in human macrophages and that the increased cytokine expression was dependent on NF-B activation (32,33). Recent reports have indicated that herpesviruses can modulate innate immunity through TLRs (5)(6)(7)(8)(9)(10)(11).…”

Section: The Ebv-encoded Dutpase Is Not Recognized By Tlr4 or Tlr3mentioning

confidence: 99%

“…However, little is known concerning the role that proteins involved with lytic replication of EBV may have in triggering TLR-mediated responses. We have previously demonstrated that the purified EBV-encoded dUTPase induces the up-regulation of IL-10 and the proinflammatory cytokines TNF-␣, IL-1␤, IL-6, and IL-8 in human monocyte-derived macrophage (hMDM)-CD14 ϩ cells (32). The increased expression and production of cytokines observed in response to EBV-encoded dUTPase treatment of hMDM were dependent on the activation of NF-B (33).…”

mentioning

confidence: 99%

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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

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138

161

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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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Section: Purification Of the Ebv-encoded Dutpasementioning

confidence: 99%

Section: Purification Of the Ebv-encoded Dutpasementioning

confidence: 99%

Section: The Ebv-encoded Dutpase Is Not Recognized By Tlr4 or Tlr3mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

138

161

View full text Add to dashboard Cite

show abstract

“…Previous studies demonstrated that EBV-encoded dUTPase stimulates the expression of proinflammatory cytokines in human PBMCs and HMDM and that the increased cytokine expression was dependent on NF-κB activation (Glaser et al, 2006;Waldman et al, 2008). Recent reports have indicated that TLR2 is also shown to play an important role in immune responses directed against EBV infection.…”

Section: Ebv Infection Of Primary B Cells Causes B Cell Activation Anmentioning

confidence: 99%

Herpesviral infection and Toll-like receptor 2

Cai

Zheng

2012

Protein Cell

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In the last decade, substantial progress has been made in understanding the molecular mechanisms involved in the initial host responses to viral infections. Herpesviral infections can provoke an inflammatory cytokine response, however, the innate pathogen-sensing mechanisms that transduce the signal for this response are poorly understood. In recent years, it has become increasingly evident that the Toll-like receptors (TLRs), which are germline-encoded pattern recognition receptors (PRRs), function as potent sensors for infection. TLRs can induce the activation of the innate immunity by recruiting specific intracellular adaptor proteins to initiate signaling pathways, which then culminating in activation of the nuclear factor kappa B (NF-κB) and interferon-regulatory factors (IRFs) that control the transcription of genes encoding type I interferon (IFN I) and other inflammatory cytokines. Furthermore, activation of innate immunity is critical for mounting adaptive immune responses. In parallel, common mechanisms used by viruses to counteract TLR-mediated responses or to actively subvert these pathways that block recognition and signaling through TLRs for their own benefit are emerging. Recent findings have demonstrated that TLR2 plays a crucial role in initiating the inflammatory process, and surprisingly that the response TLR2 triggers might be overzealous in its attempt to counter the attack by the virus. In this review, we summarize and discuss the recent advances about the specific role of TLR2 in triggering inflammatory responses in herpesvirus infection and the consequences of the alarms raised in the host that they are assigned to protect.

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Targeting Epstein‐Barr Virus dUTPase, an Immunomodulatory Protein Using Antiviral, Anti‐Inflammatory, and Neuroprotective Phytochemicals

Tiwari

Murmu

Indari

et al. 2022

Chemistry & Biodiversity

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Although primary infection of Epstein-Barr virus is generally non-lethal, viral reactivation is often associated with fatal outcomes. Regardless, there is no FDA-approved treatment available for this omnipresent viral infection. The current investigation targets viral maintenance and reactivation by inhibiting the functioning of viral deoxyuridine-triphosphatase (dUTPase) using phytochemicals. The EBV-dUTPase is essential for maintaining nucleotide balance and thus, plays a vital role in the viral replication cycle. Additionally, the protein has shown neuroinflammatory effects on the host. To selectively target the protein and possibly alter its activity, we utilized a virtual screening approach and screened 45 phytochemicals reported to have antiviral, anti-inflammatory, and neuroprotective properties. The analysis revealed several phytochemicals bound to the target protein with high affinity. In-silico ADMET and Lipinski's rule analysis predicted favorable druggability of Dehydroevodiamine (DHE) among all the phytochemicals. Further, we corroborated our findings by molecular dynamic simulation and binding affinity estimation. Our outcomes ascertained a stable binding of DHE to EBV-dUTPase primarily through electrostatic interactions. We identified that the protein-ligand binding involves the region around His71, previously reported as a potent drug target site. Conclusively, the phytochemical DHE showed a promising future as a drug development candidate against EBV-dUTPase.

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EBV-encoded dUTPase induces immune dysregulation: Implications for the pathophysiology of EBV-associated disease

Cited by 87 publications

References 43 publications

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

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

Herpesviral infection and Toll-like receptor 2

Targeting Epstein‐Barr Virus dUTPase, an Immunomodulatory Protein Using Antiviral, Anti‐Inflammatory, and Neuroprotective Phytochemicals

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