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Journal of Virology, August 2006, p. 8151-8157, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00496-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role of CCL5 (RANTES) in Viral Lung Disease

Fiona J. Culley,1,{dagger},¶ Alasdair M. J. Pennycook,1,¶ John S. Tregoning,1,¶ Jonathan S. Dodd,1 Gerhard Walzl,1,{ddagger} Timothy N. Wells,2 Tracy Hussell,1,§ and Peter J. M. Openshaw1*

Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, St Mary's Campus, Norfolk Place, London, United Kingdom,1 Serono Pharmaceutical Research Institute, Geneva, Switzerland2

Received 9 March 2005/ Accepted 2 June 2006

CCL5/RANTES is a key proinflammatory chemokine produced by virus-infected epithelial cells and present in respiratory secretions of asthmatics. To examine the role of CCL5 in viral lung disease, we measured its production during primary respiratory syncytial virus (RSV) infection and during secondary infection after sensitizing vaccination that induces Th2-mediated eosinophilia. A first peak of CCL5 mRNA and protein production was seen at 18 to 24 h of RSV infection, before significant lymphocyte recruitment occurred. Treatment in vivo with Met-RANTES (a competitive chemokine receptor blocker) throughout primary infection decreased CD4+ and CD8+ cell recruitment and increased viral replication. In RSV-infected, sensitized mice with eosinophilic disease, CCL5 production was further augmented; Met-RANTES treatment again reduced inflammatory cell recruitment and local cytokine production. A second wave of CCL5 production occurred on day 7, attributable to newly recruited T cells. Paradoxically, mice treated with Met-RANTES during primary infection demonstrated increased cellular infiltration during reinfection. We therefore show that RSV induces CCL5 production in the lung and this causes the recruitment of RSV-specific cells, including those making additional CCL5. If this action is blocked with Met-RANTES, inflammation decreases and viral clearance is delayed. However, the exact effects of chemokine modulation depend critically on time of administration, a factor that may potentially complicate the use of chemokine blockers in inflammatory diseases.

* Corresponding author. Mailing address: Department of Respiratory Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom. Phone: 44 20 7594 3854. Fax: 44 20 7262 8913. E-mail: p.openshaw{at}imperial.ac.uk.

{dagger} Present address: Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Faculty of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.

These authors contributed equally to this work.

{ddagger} Present address: Institute of Internal Medicine, University of Stellenbosch Medical School, Cape Town, South Africa.

§ Present address: The Kennedy Institute, Aspenlea Road, London W6 8LH, United Kingdom.

Journal of Virology, August 2006, p. 8151-8157, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00496-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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