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Epstein-Barr virus binding to CD21 activates the initial viral promoter via NF-kappaB induction.

Sugano N, Chen W, Roberts ML, Cooper NR - J. Exp. Med. (1997)

Bottom Line: Epstein-Barr virus (EBV), an oncogenic human herpesvirus, binds to and infects normal human B lymphocytes via CD21, the CR2 complement receptor.Studies of the mechanisms that enable EBV to infect nonactivated, noncycling B cells provide compelling evidence for a sequence of events in which EBV binding to CD21 on purified resting human B cells rapidly activates the NF-kappaB transcription factor, which, in turn, binds to and mediates transcriptional activation of Wp, the initial viral latent gene promoter.Thus, EBV binding to its cellular receptor on resting B cells triggers an NF-kappaB-dependent intracellular signaling pathway which is required for infection.

View Article: PubMed Central - PubMed

Affiliation: Scripps Research Institute, Department of Immunology, La Jolla, California 92037, USA.

ABSTRACT
Epstein-Barr virus (EBV), an oncogenic human herpesvirus, binds to and infects normal human B lymphocytes via CD21, the CR2 complement receptor. Studies of the mechanisms that enable EBV to infect nonactivated, noncycling B cells provide compelling evidence for a sequence of events in which EBV binding to CD21 on purified resting human B cells rapidly activates the NF-kappaB transcription factor, which, in turn, binds to and mediates transcriptional activation of Wp, the initial viral latent gene promoter. Thus, EBV binding to its cellular receptor on resting B cells triggers an NF-kappaB-dependent intracellular signaling pathway which is required for infection.

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Inhibition of EBV-induced NF-κB activation and EBV infection by aspirin. (A) Effect of aspirin on EBV-induced NF-κB activation. Purified resting B cells were preincubated with aspirin for 2 h before EBV addition. Nuclear extracts were prepared 30 min later and assessed for NF-κB activation. (B) Effect of aspirin on EBNA 2 transcription. Purified resting B cells were incubated with aspirin for 2 h before EBV addition. RNA was extracted 24 h after EBV addition and analyzed in RNase protection assays. (C) Effect of aspirin on EBV-induced [3H]thymidine incorporation. Purified  resting B cells were preincubated with aspirin for 2 h before EBV addition, and ability to incorporate [3H]thymidine was evaluated 14 d later.
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Figure 2: Inhibition of EBV-induced NF-κB activation and EBV infection by aspirin. (A) Effect of aspirin on EBV-induced NF-κB activation. Purified resting B cells were preincubated with aspirin for 2 h before EBV addition. Nuclear extracts were prepared 30 min later and assessed for NF-κB activation. (B) Effect of aspirin on EBNA 2 transcription. Purified resting B cells were incubated with aspirin for 2 h before EBV addition. RNA was extracted 24 h after EBV addition and analyzed in RNase protection assays. (C) Effect of aspirin on EBV-induced [3H]thymidine incorporation. Purified resting B cells were preincubated with aspirin for 2 h before EBV addition, and ability to incorporate [3H]thymidine was evaluated 14 d later.

Mentions: The biological relevance of EBV-induced NF-κB activation was addressed by evaluating the effects of aspirin on the initial stages of EBV infection; aspirin inhibits NF-κB activation induced by different stimuli in multiple cell types via unknown mechanisms in vitro and in vivo (24, 25). EBV-induced NF-κB activation was markedly inhibited by pretreating resting B cells for 2 h with 5 mM or 1 mM aspirin (Fig. 2 A). RNase protection assays showed that aspirin inhibited transcription of EBNA 2, one of the first expressed EBV latent genes (Fig. 2 B). Aspirin, which is not a general transcriptional inhibitor, only modestly reduced messenger RNA levels of the rpL32 housekeeping gene (50% at 5 mM; Fig. 2 B). Scanning and expression of the pixel density units as EBNA 2/rpL32 ratios to compensate for the effects on rpL32 transcription revealed that 0.5, 1, and 5 mM aspirin inhibited EBNA 2 transcription by 12, 58, and 73%, respectively. Pretreatment with 1 or 5 mM aspirin also inhibited EBV-induced thymidine incorporation 14 d after infection by 99%; this time point largely assesses EBV-induced transformation and immortalization (Fig. 2 C). Another NF-κB inhibitor, N-acetylcysteine (20 mM), also completely blocked NF-κB activation 30 min after EBV addition, and thymidine incorporation 14 d after infection (not shown); this agent inhibits NF-κB activation via its antioxidative properties (26), which is likely a different mechanism than aspirin. Although neither aspirin nor N-acetylcysteine are specific NF-κB inhibitors, their common ability to block EBV-induced activation is consistent with an essential role for NF-κB activation in the initial stages of EBV infection of resting B cells.


Epstein-Barr virus binding to CD21 activates the initial viral promoter via NF-kappaB induction.

Sugano N, Chen W, Roberts ML, Cooper NR - J. Exp. Med. (1997)

Inhibition of EBV-induced NF-κB activation and EBV infection by aspirin. (A) Effect of aspirin on EBV-induced NF-κB activation. Purified resting B cells were preincubated with aspirin for 2 h before EBV addition. Nuclear extracts were prepared 30 min later and assessed for NF-κB activation. (B) Effect of aspirin on EBNA 2 transcription. Purified resting B cells were incubated with aspirin for 2 h before EBV addition. RNA was extracted 24 h after EBV addition and analyzed in RNase protection assays. (C) Effect of aspirin on EBV-induced [3H]thymidine incorporation. Purified  resting B cells were preincubated with aspirin for 2 h before EBV addition, and ability to incorporate [3H]thymidine was evaluated 14 d later.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199015&req=5

Figure 2: Inhibition of EBV-induced NF-κB activation and EBV infection by aspirin. (A) Effect of aspirin on EBV-induced NF-κB activation. Purified resting B cells were preincubated with aspirin for 2 h before EBV addition. Nuclear extracts were prepared 30 min later and assessed for NF-κB activation. (B) Effect of aspirin on EBNA 2 transcription. Purified resting B cells were incubated with aspirin for 2 h before EBV addition. RNA was extracted 24 h after EBV addition and analyzed in RNase protection assays. (C) Effect of aspirin on EBV-induced [3H]thymidine incorporation. Purified resting B cells were preincubated with aspirin for 2 h before EBV addition, and ability to incorporate [3H]thymidine was evaluated 14 d later.
Mentions: The biological relevance of EBV-induced NF-κB activation was addressed by evaluating the effects of aspirin on the initial stages of EBV infection; aspirin inhibits NF-κB activation induced by different stimuli in multiple cell types via unknown mechanisms in vitro and in vivo (24, 25). EBV-induced NF-κB activation was markedly inhibited by pretreating resting B cells for 2 h with 5 mM or 1 mM aspirin (Fig. 2 A). RNase protection assays showed that aspirin inhibited transcription of EBNA 2, one of the first expressed EBV latent genes (Fig. 2 B). Aspirin, which is not a general transcriptional inhibitor, only modestly reduced messenger RNA levels of the rpL32 housekeeping gene (50% at 5 mM; Fig. 2 B). Scanning and expression of the pixel density units as EBNA 2/rpL32 ratios to compensate for the effects on rpL32 transcription revealed that 0.5, 1, and 5 mM aspirin inhibited EBNA 2 transcription by 12, 58, and 73%, respectively. Pretreatment with 1 or 5 mM aspirin also inhibited EBV-induced thymidine incorporation 14 d after infection by 99%; this time point largely assesses EBV-induced transformation and immortalization (Fig. 2 C). Another NF-κB inhibitor, N-acetylcysteine (20 mM), also completely blocked NF-κB activation 30 min after EBV addition, and thymidine incorporation 14 d after infection (not shown); this agent inhibits NF-κB activation via its antioxidative properties (26), which is likely a different mechanism than aspirin. Although neither aspirin nor N-acetylcysteine are specific NF-κB inhibitors, their common ability to block EBV-induced activation is consistent with an essential role for NF-κB activation in the initial stages of EBV infection of resting B cells.

Bottom Line: Epstein-Barr virus (EBV), an oncogenic human herpesvirus, binds to and infects normal human B lymphocytes via CD21, the CR2 complement receptor.Studies of the mechanisms that enable EBV to infect nonactivated, noncycling B cells provide compelling evidence for a sequence of events in which EBV binding to CD21 on purified resting human B cells rapidly activates the NF-kappaB transcription factor, which, in turn, binds to and mediates transcriptional activation of Wp, the initial viral latent gene promoter.Thus, EBV binding to its cellular receptor on resting B cells triggers an NF-kappaB-dependent intracellular signaling pathway which is required for infection.

View Article: PubMed Central - PubMed

Affiliation: Scripps Research Institute, Department of Immunology, La Jolla, California 92037, USA.

ABSTRACT
Epstein-Barr virus (EBV), an oncogenic human herpesvirus, binds to and infects normal human B lymphocytes via CD21, the CR2 complement receptor. Studies of the mechanisms that enable EBV to infect nonactivated, noncycling B cells provide compelling evidence for a sequence of events in which EBV binding to CD21 on purified resting human B cells rapidly activates the NF-kappaB transcription factor, which, in turn, binds to and mediates transcriptional activation of Wp, the initial viral latent gene promoter. Thus, EBV binding to its cellular receptor on resting B cells triggers an NF-kappaB-dependent intracellular signaling pathway which is required for infection.

Show MeSH
Related in: MedlinePlus