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Manipulation of the Toll-Like Receptor 7 Signaling Pathway by Epstein-Barr Virus

Authors
 Heather J. Martin  ;  Jae Myun Lee  ;  S. Diane Hayward  ;  Dermot Walls 
Citation
 Journal of Virology, Vol.81(18) : 9748-9758, 2007 
Journal Title
 Journal of Virology 
ISSN
 0022-538X 
Issue Date
2007
MeSH
Adjuvants, Immunologic/pharmacology ; Alternative Splicing/drug effects ; Alternative Splicing/genetics ; Alternative Splicing/physiology ; Aminoquinolines/pharmacology ; B-Lymphocytes/metabolism* ; B-Lymphocytes/virology ; CD40 Antigens/genetics ; CD40 Antigens/metabolism ; CD40 Ligand/genetics ; CD40 Ligand/metabolism ; Cell Line, Transformed ; Cell Proliferation/radiation effects ; Cell Survival/drug effects ; Cell Survival/genetics ; Cell Survival/radiation effects ; Epstein-Barr Virus Infections/genetics ; Epstein-Barr Virus Infections/metabolism* ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/genetics ; Gene Expression Regulation/radiation effects ; HeLa Cells ; Herpesvirus 4, Human/genetics ; Herpesvirus 4, Human/metabolism* ; Humans ; Imiquimod ; Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/metabolism ; Lymphocyte Activation*/drug effects ; Lymphocyte Activation*/genetics ; Lymphocyte Activation*/radiation effects ; Signal Transduction*/drug effects ; Signal Transduction*/genetics ; Signal Transduction*/radiation effects ; Toll-Like Receptor 7/agonists ; Toll-Like Receptor 7/metabolism* ; Toll-Like Receptor 9/genetics ; Toll-Like Receptor 9/metabolism ; Ultraviolet Rays ; Viral Matrix Proteins/genetics ; Viral Matrix Proteins/metabolism ; Virus Latency/drug effects ; Virus Latency/genetics ; Virus Latency/radiation effects
Abstract
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.
Files in This Item:
T200700706.pdf Download
DOI
10.1128/JVI.01122-07
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/96725
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