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Journal of Virology, July 2007, p. 7786-7800, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.02780-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Small Interfering RNA Profiling Reveals Key Role of Clathrin-Mediated Endocytosis and Early Endosome Formation for Infection by Respiratory Syncytial Virus{triangledown}

Andrey A. Kolokoltsov,1,{dagger} Drew Deniger,1,{dagger} Elisa H. Fleming,1 Norbert J. Roberts Jr.,1 Jon M. Karpilow,2 and Robert A. Davey1*

Department of Microbiology and Immunology, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, Texas,1 Dharmacon, Inc., Lafayette, Ohio2

Received 15 December 2006/ Accepted 1 May 2007

Respiratory syncytial virus (RSV) is a common cause of respiratory tract infections in infants and the elderly. Like many other pH-independent enveloped viruses, RSV is thought to enter at the cell surface, independently of common endocytic pathways. We have used a targeted small interfering RNA (siRNA) library to identify key cellular genes involved in cytoskeletal dynamics and endosome trafficking that are important for RSV infection. Surprisingly, RSV infection was potently inhibited by siRNAs targeting genes associated with clathrin-mediated endocytosis, including clathrin light chain. The important role of clathrin-mediated endocytosis was confirmed by the expression of well-characterized dominant-negative mutants of genes in this pathway and by using the clathrin endocytosis inhibitor chlorpromazine. We conclude that, while RSV may be competent to enter at the cell surface, clathrin function and endocytosis are a necessary and important part of a productive RSV infection, even though infection is strictly independent of pH. These findings raise the possibility that other pH-independent viruses may share a similar dependence on endocytosis for infection and provide a new potential avenue for treatment of infection.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX. Phone: (409) 772-4915. Fax: (409) 772-5065. E-mail: radavey{at}utmb.edu

{triangledown} Published ahead of print on 9 May 2007.

{dagger} These authors contributed equally to this work.

Journal of Virology, July 2007, p. 7786-7800, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.02780-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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