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Journal of Virology, April 2008, p. 3853-3863, Vol. 82, No. 8
0022-538X/08/$08.00+0     doi:10.1128/JVI.02577-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Role for MyD88 Signaling in Murine Gammaherpesvirus 68 Latency{triangledown}

Lisa M. Gargano, Janice M. Moser,{dagger} and Samuel H. Speck*

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia

Received 3 December 2007/ Accepted 25 January 2008

Toll-like receptors (TLRs) are known predominantly for their role in activating the innate immune response. Recently, TLR signaling via MyD88 has been reported to play an important function in development of a B-cell response. Since B cells are a major latency reservoir for murine gammaherpesvirus 68 (MHV68), we investigated the role of TLR signaling in the establishment and maintenance of MHV68 latency in vivo. Mice deficient in MyD88 (MyD88–/–) or TLR3 (TLR3–/–) were infected with MHV68. Analysis of splenocytes recovered at day 16 postinfection from MyD88–/– mice compared to those from wild-type control mice revealed a lower frequency of (i) activated B cells, (ii) germinal-center B cells, and (iii) class-switched B cells. Accompanying this substantial defect in the B-cell response was an approximately 10-fold decrease in the establishment of splenic latency. In contrast, no defect in viral latency was observed in TLR3–/– mice. Analysis of MHV68-specific antibody responses also demonstrated a substantial decrease in the kinetics of the response in MyD88–/– mice. Analysis of wild-type x MyD88–/– mixed-bone-marrow chimeric mice demonstrated that there is a selective failure of MyD88–/– B cells to participate in germinal-center reactions as well as to become activated and undergo class switching. In addition, while MHV68 established latency efficiently in the MyD88-sufficient B cells, there was again a ca. 10-fold reduction in the frequency of MyD88–/– B cells harboring latent MHV68. This phenotype indicates that MyD88 is important for the establishment of MHV68 latency and is directly related to the role of MyD88 in the generation of a B-cell response. Furthermore, the generation of a B-cell response to MHV68 was intrinsic to B cells and was independent of the interleukin-1 receptor, a cytokine receptor that also signals through MyD88. These data provide evidence for a unique role for MyD88 in the establishment of MHV68 latency.

* Corresponding author. Mailing address: Department of Microbiology & Immunology, Emory University School of Medicine, 1462 Clifton Road, Suite 429, Atlanta, GA 30329. Phone: (404) 727-7665. Fax: (404) 727-7768. E-mail: sspeck{at}emory.edu

{triangledown} Published ahead of print on 6 February 2008.

{dagger} Present address: VaxDesign Corporation, 2721 Discovery Dr., Suite 400, Orlando, FL 32826.

Journal of Virology, April 2008, p. 3853-3863, Vol. 82, No. 8
0022-538X/08/$08.00+0     doi:10.1128/JVI.02577-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hwang, I.-Y., Park, C., Harrison, K., Kehrl, J. H. (2009). TLR4 signaling augments B lymphocyte migration and overcomes the restriction that limits access to germinal center dark zones. JEM 206: 2641-2657 [Abstract] [Full Text]  
  • Krug, L. T., Collins, C. M., Gargano, L. M., Speck, S. H. (2009). NF-{kappa}B p50 Plays Distinct Roles in the Establishment and Control of Murine Gammaherpesvirus 68 Latency. J. Virol. 83: 4732-4748 [Abstract] [Full Text]  
  • Gargano, L. M., Forrest, J. C., Speck, S. H. (2009). Signaling through Toll-Like Receptors Induces Murine Gammaherpesvirus 68 Reactivation In Vivo. J. Virol. 83: 1474-1482 [Abstract] [Full Text]  


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