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Journal of Virology, February 2009, p. 1474-1482, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01717-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Signaling through Toll-Like Receptors Induces Murine Gammaherpesvirus 68 Reactivation In Vivo{triangledown}

Lisa M. Gargano, J. Craig Forrest, and Samuel H. Speck*

Emory Vaccine Center and Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, Georgia 30322

Received 12 August 2008/ Accepted 11 November 2008

Murine gammaherpesvirus 68 (MHV68) establishes a lifelong infection in mice and is used as a model pathogen to study the role of viral and host factors in chronic infection. The maintenance of chronic MHV68 infection, at least in some latency reservoirs, appears to be dependent on the capacity of the virus to reactivate from latency in vivo. However, the signals that lead to MHV68 reactivation in vivo are not well characterized. Toll-like receptors (TLRs), by recognizing the specific patterns of microbial components, play an essential role in the activation of innate immunity. In the present study, we investigated the capacity of TLR ligands to induce MHV68 reactivation, both in vitro and in vivo. The stimulation of latently infected B cell lines with ligands for TLRs 3, 4, 5, and 9 enhanced MHV68 reactivation; the ex vivo stimulation of latently infected primary splenocytes, recovered from infected mice, with poly(I:C), lipopolysaccharide, flagellin, or CpG DNA led to early B-cell activation, B-cell proliferation, and a significant increase in the frequency of latently infected cells reactivating the virus. In vivo TLR stimulation also induced B-cell activation and MHV68 reactivation, resulting in heightened levels of virus replication in the lungs which correlated with an increase in MHV68-specific CD8+ T-cell responses. Importantly, TLR stimulation also led to an increase in MHV68 latency, as evidenced by an increase in viral genome-positive cells 2 weeks post-in vivo stimulation by specific TLR ligands. Thus, these data demonstrate that TLR stimulation can drive MHV68 reactivation from latency and suggests that periodic pathogen exposure may contribute to the homeostatic maintenance of chronic gammaherpesvirus infection through stimulating virus reactivation and reseeding latency reservoirs.

* Corresponding author. Mailing address: Emory Vaccine Center, 1462 Clifton Road, Suite 429, Atlanta, GA 30322. Phone: (404) 727-7665. Fax: (404) 712-9736. E-mail: sspeck{at}emory.edu

{triangledown} Published ahead of print on 19 November 2008.

Journal of Virology, February 2009, p. 1474-1482, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01717-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Gregory, S. M., West, J. A., Dillon, P. J., Hilscher, C., Dittmer, D. P., Damania, B. (2009). Toll-like receptor signaling controls reactivation of KSHV from latency. Proc. Natl. Acad. Sci. USA 106: 11725-11730 [Abstract] [Full Text]  


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