title: EBV lytic-phase protein BGLF5 contributes to TLR9 downregulation during productive infection.
abstract: Viruses use a wide range of strategies to modulate the host immune response. The human gammaherpesvirus EBV, causative agent of infectious mononucleosis and several malignant tumors, encodes proteins that subvert immune responses, notably those mediated by T cells. Less is known about EBV interference with innate immunity, more specifically at the level of TLR-mediated pathogen recognition. The viral dsDNA sensor TLR9 is expressed on B cells, a natural target of EBV infection. Here, we show that EBV particles trigger innate immune signaling pathways through TLR9. Furthermore, using an in vitro system for productive EBV infection, it has now been possible to compare the expression of TLRs by EBV(-) and EBV(+) human B cells during the latent and lytic phases of infection. Several TLRs were found to be differentially expressed either in latently EBV-infected cells or after induction of the lytic cycle. In particular, TLR9 expression was profoundly decreased at both the RNA and protein levels during productive EBV infection. We identified the EBV lytic-phase protein BGLF5 as a protein that contributes to downregulating TLR9 levels through RNA degradation. Reducing the levels of a pattern-recognition receptor capable of sensing the presence of EBV provides a mechanism by which the virus could obstruct host innate antiviral responses.
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: van Gent
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Griffin
authors.forename: Eufemia G
authors.initials: EG
authors.lastname: Berkhoff
authors.forename: Daphne
authors.initials: D
authors.lastname: van Leeuwen
authors.forename: Ingrid G J
authors.initials: IG
authors.lastname: Boer
authors.forename: Marlyse
authors.initials: M
authors.lastname: Buisson
authors.forename: Franca C
authors.initials: FC
authors.lastname: Hartgers
authors.forename: Wim P
authors.initials: WP
authors.lastname: Burmeister
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Wiertz
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Ressing
mesh_terms: D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology / Q000821:virology; D002051:Burkitt Lymphoma / Q000276:immunology / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003851:Deoxyribonucleases / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D014764:Viral Proteins / Q000502:physiology*; D014771:Virion / Q000276:immunology; D014775:Virus Activation / Q000276:immunology; D017735:Virus Latency / Q000276:immunology*
chemical_list: D012367:RNA, Viral; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D014764:Viral Proteins; D003851:Deoxyribonucleases; C083203:deoxyribonuclease, Epstein-Barr virus