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Journal of Virology, August 2008, p. 7613-7623, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.00618-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Dysregulation of TLR3 Impairs the Innate Immune Response to West Nile Virus in the Elderly {triangledown}

Kok-Fai Kong, Karine Delroux, Xiaomei Wang, Feng Qian, Alvaro Arjona, Stephen E. Malawista, Erol Fikrig, and Ruth R. Montgomery*

Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520

Received 19 March 2008/ Accepted 16 May 2008

West Nile virus (WNV), a mosquito-borne flavivirus, has recently emerged in North America, and the elderly are particularly susceptible to severe neurological disease and death from infection with this virus. We have investigated the innate immune response of primary human macrophages to WNV in vitro and have found significant differences between the responsiveness of macrophages derived from younger donors and that from older donors. Binding of the glycosylated WNV envelope protein to the C-type lectin dendritic cell-specific intercellular adhesion molecule 3 (ICAM3) grabbing nonintegrin (DC-SIGN) leads to a reduction in the expression of Toll-like receptor 3 (TLR3) in macrophages from young donors via the signal transducer and activator of transcription 1 (STAT1)-mediated pathway. This signaling is impaired in the elderly, and the elevated levels of TLR3 result in an elevation of cytokine levels. This alteration of the innate immune response with aging may contribute to the permeability of the blood-brain barrier and suggests a possible mechanism for the increased severity of WNV infection in older individuals.

* Corresponding author. Mailing address: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8031. Phone: (203) 785-7039. Fax: (203) 785-7053. E-mail: ruth.montgomery{at}yale.edu

{triangledown} Published ahead of print on 28 May 2008.

Journal of Virology, August 2008, p. 7613-7623, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.00618-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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