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Journal of Virology, September 2007, p. 9748-9758, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.01122-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Heather J. Martin,1,2 Jae Myun Lee,3 Dermot Walls,4 and S. Diane Hayward1,2*

Viral Oncology Program, Sidney Kimmel Comprehensive Cancer Center,1 Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21231,2 Department of Microbiology, Yonsei University, Seoul, Korea,3 School of Biotechnology, Dublin City University, Dublin, Ireland4

Received 23 May 2007/ Accepted 27 June 2007

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.

* Corresponding author. Mailing address: Johns Hopkins School of Medicine, Bunting-Blaustein Building CRB308, 1650 Orleans Street, Baltimore, MD 21231-1000. Phone: (410) 614-0592. Fax: (410) 502-6802. E-mail: dhayward{at}jhmi.edu

{triangledown} Published ahead of print on 3 July 2007.

Journal of Virology, September 2007, p. 9748-9758, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.01122-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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