Differentiation-Dependent KLF4 Expression Promotes Lytic Epstein-Barr Virus Infection in Epithelial Cells


Lytic EBV infection of differentiated oral epithelial cells results in the release of infectious viral particles and is required for efficient transmission of EBV from host to host. Lytic infection also causes a tongue lesion known as oral hairy leukoplakia (OHL). However, surprisingly little is known in regard to how EBV gene expression is regulated in epithelial cells. Using a stably EBV- infected, telomerase-immortalized normal oral keratinocyte cell line, we show here that undifferentiated basal epithelial cells support latent EBV infection, while differentiation of epithelial cells promotes lytic reactivation. Furthermore, we demonstrate that the KLF4 cellular transcription factor, which is required for normal epithelial cell differentiation and is expressed in differentiated, but not undifferentiated, normal epithelial cells, induces lytic EBV reactivation by activating transcription from the two EBV immediate-early gene promoters. We also show that the combination of KLF4 and another differentiation-dependent cellular transcription factor, BLIMP1, synergistically activates lytic gene expression in epithelial cells. We confirm that KLF4 and BLIMP1 expression in normal tongue epithelium is confined to differentiated cells, and that KLF4 and BLIMP1 are expressed in a patient-derived OHL tongue lesion. These results suggest that differentiation-dependent expression of KLF4 and BLIMP1 in epithelial cells promotes lytic EBV infection.


Vyšlo v časopise: Differentiation-Dependent KLF4 Expression Promotes Lytic Epstein-Barr Virus Infection in Epithelial Cells. PLoS Pathog 11(10): e32767. doi:10.1371/journal.ppat.1005195
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1005195

Souhrn

Lytic EBV infection of differentiated oral epithelial cells results in the release of infectious viral particles and is required for efficient transmission of EBV from host to host. Lytic infection also causes a tongue lesion known as oral hairy leukoplakia (OHL). However, surprisingly little is known in regard to how EBV gene expression is regulated in epithelial cells. Using a stably EBV- infected, telomerase-immortalized normal oral keratinocyte cell line, we show here that undifferentiated basal epithelial cells support latent EBV infection, while differentiation of epithelial cells promotes lytic reactivation. Furthermore, we demonstrate that the KLF4 cellular transcription factor, which is required for normal epithelial cell differentiation and is expressed in differentiated, but not undifferentiated, normal epithelial cells, induces lytic EBV reactivation by activating transcription from the two EBV immediate-early gene promoters. We also show that the combination of KLF4 and another differentiation-dependent cellular transcription factor, BLIMP1, synergistically activates lytic gene expression in epithelial cells. We confirm that KLF4 and BLIMP1 expression in normal tongue epithelium is confined to differentiated cells, and that KLF4 and BLIMP1 are expressed in a patient-derived OHL tongue lesion. These results suggest that differentiation-dependent expression of KLF4 and BLIMP1 in epithelial cells promotes lytic EBV infection.


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