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Journal of Virology, March 2005, p. 3350-3357, Vol. 79, No. 6
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.6.3350-3357.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Differential Role for TLR3 in Respiratory Syncytial Virus-Induced Chemokine Expression

Brian D. Rudd,1 Ezra Burstein,1 Colin S. Duckett,1 Xiaoxia Li,2 and Nicholas W. Lukacs1*

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan,1 Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio2

Received 25 August 2004/ Accepted 29 October 2004

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in young infants worldwide. Previous studies have reported that the induction of interleukin-8/CXCL8 and RANTES/CCL5 correlates with disease severity in humans. The production of these chemokines is elicited by viral replication and is NF-{kappa}B dependent. RSV, a negative-sense single-stranded RNA virus, requires full-length positive-sense RNA for synthesis of new viral RNA. The aim of our studies was to investigate whether active viral replication by RSV could evoke chemokine production through TLR3-mediated signaling pathways. In TLR3-transfected HEK 293 cells, live RSV preferentially activated chemokines in both a time- and dose-dependent manner compared to vector controls. RSV was also shown to upregulate TLR3 in human lung fibroblasts and epithelial cells (MRC-5 and A549). Targeting the expression of TLR3 with small interfering RNA decreased synthesis of IP-10/CXCL10 and CCL5 but did not significantly reduce levels of CXCL8. Blocking the expression of the adapter protein MyD88 established a role for MyD88 in CXCL8 production, whereas CCL5 synthesis was found to be MyD88 independent. Production of CCL5 by RSV was induced directly through TLR3 signaling pathways and did not require interferon (IFN) signaling through the IFN-{alpha}/ß receptor. TLR3 did not affect viral replication, since equivalent viral loads were recovered from RSV-infected cells despite altered TLR3 expression. Taken together, our studies indicate that TLR3 mediates inflammatory cytokine and chemokine production in RSV-infected epithelial cells.

* Corresponding author. Mailing address: Department of Pathology, University of Michigan Medical School, 1301 Catherine St., 5214 Medical Science 1, Ann Arbor, MI 48109. Phone: (734) 936-1020. Fax: (734) 615-8166. E-mail: nlukacs{at}umich.edu.

Journal of Virology, March 2005, p. 3350-3357, Vol. 79, No. 6
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.6.3350-3357.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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