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Journal of Virology, February 2007, p. 1451-1460, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.02243-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Tumor Necrosis Factor (TNF) Protects Resistant C57BL/6 Mice against Herpes Simplex Virus-Induced Encephalitis Independently of Signaling via TNF Receptor 1 or 2{triangledown}

Patric Lundberg,1,2 Paula V. Welander,1,{dagger} Carl K. Edwards III,4,{ddagger} Nico van Rooijen,5 and Edouard Cantin1,2,3*

Departments of Virology,1 Immunology,2 Neurology,Beckman Research Institute, City of Hope Medical Center, Duarte, California,3 Amgen Inc., Thousand Oaks, California,4 Vrije Universiteit, VUMC Department of Molecular Cell Biology, Amsterdam, The Netherlands5

Received 12 October 2006/ Accepted 6 November 2006

Tumor necrosis factor (TNF) is a multifunctional cytokine that has a role in induction and regulation of host innate and adaptive immune responses. The importance of TNF antiviral mechanisms is reflected by the diverse strategies adopted by different viruses, particularly members of the herpesvirus family, to block TNF responses. TNF binds and signals through two receptors, Tnfrsf1a (TNF receptor 1 [TNFR1], or p55) and Tnfrsf1b (TNFR2, or p75). We report here that herpes simplex virus 1 (HSV-1) infection of TNF–/– mice on the resistant C57BL/6 genetic background results in significantly increased susceptibility (P < 0.0001, log rank test) to fatal HSV encephalitis (HSE) and prolonged persistence of elevated levels of virus in neural tissues. In contrast, although virus titers in neural tissues of p55–/–N13 mice were elevated to levels comparable to what was found for the TNF–/– mice, the p55–/–N13 mice were as resistant as control C57BL/6 mice (P > 0.05). The incidence of fatal HSE was significantly increased by in vivo neutralization of TNF using soluble TNFR1 (sTNFR1) or depletion of macrophages in C57BL/6 mice (P = 0.0038 and P = 0.0071, respectively). Strikingly, in vivo neutralization of TNF in HSV-1-infected p55–/– p75–/– mice by use of three independent approaches (treatment with soluble p55 receptor, anti-TNF monoclonal antibody, or in vivo small interfering RNA against TNF) resulted in significantly increased mortality rates (P = 0.005), comparable in magnitude to those for C57BL/6 mice treated with sTNFR1 (P = 0.0018). Overall, these results indicate that while TNF is required for resistance to fatal HSE, both p55 and p75 receptors are dispensable. Precisely how TNF mediates protection against HSV-1 mortality in p55–/– p75–/– mice remains to be determined.

* Corresponding author. Mailing address: City of Hope Medical Center and Beckman Research Institute, Department of Virology, 1500 E. Duarte Rd., Duarte, CA 91010. Phone: (626) 301-8480. Fax: (626) 301-8852. E-mail: ecantin{at}coh.org.

{triangledown} Published ahead of print on 15 November 2006.

{dagger} Present address: Department of Microbiology, University of Urbana-Champaign, B103 CLSL, 601 Goodwin Ave., Urbana, IL 61801.

{ddagger} Present address: Department of Dermatology, University of Colorado Health Sciences Center at Fitzsimons, 12801 East 17th Avenue, P.O. Box 6511, Aurora, CO 80045.

Journal of Virology, February 2007, p. 1451-1460, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.02243-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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