Lytic Epstein–Barr virus infection in epithelial cells but not in B-lymphocytes is dependent on Blimp1

Abstract

Epstein-Barr virus (EBV) replicates in superficial differentiated cells of oral hairy leukoplakia (OHL). Differentiation of squamous epithelial cells depends on B-lymphocyte-induced maturation protein 1 (Blimp1).Here we show that expression of the EBV immediate-early protein BZLF1 is restricted to Blimp1-positive epithelial cells in OHL. Luciferase assays revealed Blimp1-dependent induction of the BZLF1 promoter Zp in epithelial cell lines. Expression of ZEB1, a negative regulator of Zp, and of Xbp-1, which mediates the Blimp1 effect on Zp in B-cells, was not affected by enforced Blimp1 expression. Moreover, Xbp-1 protein expression was not detected in differentiated epithelial cells of OHL. Thus, Blimp1 induces BZLF1 expression in epithelial cells independently of ZEB1 and Xbp-1. In contrast to epithelial cells of OHL, BZLF1 expression was also observed in Blimp1-negative lymphoid cells in infectious mononucleosis tonsils, suggesting that EBV replication in B-cells may be induced independently of terminal differentiation.Epstein-Barr virus (EBV) is a B-lymphotropic human herpesvirus infecting .90 % of the adult population worldwide. Primary infection in childhood is usually asymptomatic but may cause a clinical syndrome, infectious mononucleosis (IM), when delayed into adolescence or early adulthood. Following primary infection, a lifelong persistent latent infection of memory B-cells is established. Infectious virus particles are released into the saliva, but their cellular source has been controversial (Niedobitek & Young, 1994). It is now clear that EBV may replicate in B-cells as well as in oral squamous epithelial cells. In both cellular compartments, the switch from latent to lytic infection is triggered by expression of the immediate-early gene BZLF1, which is necessary and sufficient to activate the EBV lytic cascade (Rooney et al., 1989;Miller, 1990). Various lines of evidence have indicated that EBV replication depends on cellular differentiation. Immunohistochemical analysis of B-cells in IM tonsils suggested a restriction of virus replication to cells with plasma-cell morphology (Crawford & Ando, 1986;Niedobitek et al., 1997). Furthermore, terminal differentiation of B-cells towards plasma cells initiates the lytic cycle in vivo (Laichalk & Thorley-Lawson, 2005). Similarly, it has been suggested that, in epithelial cells of oral hairy leukoplakia (OHL), an AIDS-associated lesion of the tongue mucosa, EBV replicates in a differentiation-dependent manner (Young et al., 1991).Plasma-cell differentiation is regulated by B-lymphocyteinduced maturation protein (Blimp)1 (Shapiro-Shelef et al., 2003). By repressing Pax5, Blimp1 indirectly activates the Xbox-binding protein Xbp-1 (Lin et al., 2002). Induction of BZLF1 expression by binding of Xbp-1 to the BZLF1 promoter Zp has been demonstrated in B-cells, but not in epithelial cells (Sun & Thorley-Lawson, 2007). In contrast, Bhende et al. (2007) showed that Xbp-1 transactivates BZLF1 only in combination with activated protein kinase D in B-lymphocytes and e...

Cellular Differentiation Regulator BLIMP1 Induces Epstein-Barr Virus Lytic Reactivation in Epithelial and B Cells by Activating Transcription from both the R and Z Promoters

“…1). Consistent with our findings, Buettner et al (59) observed that all Z ϩ cells within an OHL lesion are also BLIMP1 ϩ , while only onethird to two-thirds of Z ϩ B cells from tonsils of IM patients contain detectable BLIMP1. Thus, we conclude that BLIMP1 expression leads to induction of EBV lytic gene expression in many (possibly all) EBV ϩ epithelial cell types but not all EBV ϩ B-cell types.…”

“…9). Combining all of our findings together with those of Buettner et al (59), we conclude that this activation of BLIMP1 expression may well be necessary as well as sufficient in epithelial cells, but not in B cells, for induction of EBV reactivation.…”

“…Other investigators reported that while expression of EBV Z protein was restricted to BLIMP1-positive epithelial cells in oral hairy leukoplakia (OHL) tissue samples, this relationship did not hold in IM tonsillar B cells, suggesting that BLIMP1 may be necessary for induction of EBV lytic gene expression during differentiation of epithelial but not B cells (59).…”

Epstein–Barr virus replicating in epithelial cells

“…Work done when OHL lesions were more readily available indicated that replication in these lesions was restricted to the upper, more differentiated layers (15,16). More recently, virus expression has been shown to be limited to cells expressing B-lymphocyteinduced maturation protein 1 (Blimp1), which is up-regulated during epithelial differentiation, and the promoter of one of the immediate early genes of EBV is responsive to Blimp1 (17). The work of Temple et al now provides further support for a model in which replication is linked to differentiation.…”

Epstein-Barr Virus Utilizes Ikaros in Regulating Its Latent-Lytic Switch in B Cells

“…EBV establishes long-term latency in B cells, undergoing reactivation when they differentiate into plasma cells (2). Some Bcell-specific factors (e.g., Oct-2 and Pax-5) promote EBV latency (14,15), while some plasma-cell-specific factors (e.g., XBP-1s and BLIMP-1) promote EBV lytic replication (6,7,70,71). To further understand how Ikaros contributes to EBV latency, we examined the effect of changing its level on the expression of some cellular factors known to play key roles in regulating EBV's latent-lytic switch or B-cell differentiation into plasma cells.…”