Manipulation of the toll-like receptor 7 signaling pathway by Epstein-Barr virus.
Epstein-Barr virus (EBV) infection of primary B cells causes B-cell activation and proliferation. Activation of B cells requires binding of antigen to the B-cell receptor and a survival signal from ligand-bound CD40, signals that are provided by the EBV LMP1 and LMP2A latency proteins. Recently, Toll-like receptor (TLR) signaling has been reported to provide a third B-cell activation stimulus. The interaction between the EBV and TLR pathways was therefore investigated. Both UV-inactivated and untreated EBV upregulated the expression of TLR7 and downregulated the expression of TLR9 in naive B cells. UV-inactivated virus transiently stimulated naive B-cell proliferation in the presence of the TLR7 ligand R837, while addition of the TLR7 antagonist IRS 661 impaired cell growth induced by untreated EBV. Interferon regulatory factor 5 (IRF-5) is a downstream mediator of TLR7 signaling. IRF-5 was induced following EBV infection, and IRF-5 was expressed in B-cell lines with type III latency. Expression of IRF-5 in this setting is surprising since IRF-5 has tumor suppressor and antiviral properties. B-cell proliferation assays provided evidence that EBV modulates TLR7 signaling responses. Examination of IRF-5 transcripts identified a novel splice variant, V12, that was induced by EBV infection, was constitutively nuclear, and acted as a dominant negative form in IRF-5 reporter assays. IRF-4 negatively regulates IRF-5 activation, and IRF-4 was also present in type III latently infected cells. EBV therefore initially uses TLR7 signaling to enhance B-cell proliferation and subsequently modifies the pathway to regulate IRF-5 activity.
Martin
Heather J
HJ
Johns Hopkins School of Medicine, Bunting-Blaustein Building CRB308, 1650 Orleans Street, Baltimore, MD 21231-1000, USA.
Lee
Jae Myun
JM
Walls
Dermot
D
Hayward
S Diane
SD
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000634:Aminoquinolines / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism* / Q000821:virology; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000077271:Imiquimod; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism; D017735:Virus Latency / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D000099218:Interferon Regulatory Factor-4
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D019013:CD40 Antigens; D023201:CD40 Ligand; D000077271:Imiquimod; D050835:Interferon Regulatory Factors; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D014763:Viral Matrix Proteins; D000099218:Interferon Regulatory Factor-4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C431713:IRF5 protein, human; C495348:TLR7 protein, human; C495371:TLR9 protein, human