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Journal of Virology, September 2008, p. 9075-9085, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00732-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Heparan Sulfate-Binding Foot-and-Mouth Disease Virus Enters Cells via Caveola-Mediated Endocytosis{triangledown}

Vivian O'Donnell,1,2* Michael LaRocco,1 and Barry Baxt1

Foreign Animal Disease Research Unit, United States Department of Agriculture, Agricultural Research Service, Plum Island Animal Disease Center, Greenport, New York 11944,1 Department of Pathobiology and Veterinary Science, University of Connecticut at Storrs, Storrs, Connecticut 062692

Received 3 April 2008/ Accepted 30 June 2008

Foot-and-mouth disease virus (FMDV) utilizes different cell surface macromolecules to facilitate infection of cultured cells. Virus, which is virulent for susceptible animals, infects cells via four members of the {alpha}V subclass of cellular integrins. In contrast, tissue culture adaptation of some FMDV serotypes results in the loss of viral virulence in the animal, accompanied by the loss of virus' ability to use integrins as receptors. These avirulent viral variants acquire positively charged amino acids on surface-exposed structural proteins, resulting in the utilization of cell surface heparan sulfate (HS) molecules as receptors. We have recently shown that FMDV serotypes utilizing integrin receptors enter cells via a clathrin-mediated mechanism into early endosomes. Acidification within the endosome results in a breakdown of the viral capsid, releasing the RNA, which enters the cytoplasm by a still undefined mechanism. Since there is evidence that HS internalizes bound ligands via a caveola-mediated mechanism, it was of interest to analyze the entry of FMDV by cell-surface HS. Using a genetically engineered variant of type O1Campos (O1C3056R) which can utilize both integrins and HS as receptors and a second variant (O1C3056R-KGE) which can utilize only HS as a receptor, we followed viral entry using confocal microscopy. After virus bound to cells at 4°C, followed by a temperature shift to 37°C, type O1C3056R-KGE colocalized with caveolin-1, while O1C3056R colocalized with both clathrin and caveolin-1. Compounds which either disrupt or inhibit the formation of lipid rafts inhibited the replication of O1C3056R-KGE. Furthermore, a caveolin-1 knockdown by RNA interference also considerably reduced the efficiency of O1C3056R-KGE infection. These results indicate that HS-binding FMDV enters the cells via the caveola-mediated endocytosis pathway and that caveolae can associate and traffic with endosomes. In addition, these results further suggest that the route of FMDV entry into cells is a function solely of the viral receptor.

* Corresponding author. Mailing address: USDA, ARS, Plum Island Animal Disease Center, P.O. Box 848, Greenport, NY 11944-0848. Phone: (631) 477-4484. Fax: (631) 323-3006. E-mail: vivian.odonnell{at}ars.usda.gov

{triangledown} Published ahead of print on 9 July 2008.

Journal of Virology, September 2008, p. 9075-9085, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00732-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Martin-Acebes, M. A., Gonzalez-Magaldi, M., Vazquez-Calvo, A., Armas-Portela, R., Sobrino, F. (2009). Internalization of Swine Vesicular Disease Virus into Cultured Cells: a Comparative Study with Foot-and-Mouth Disease Virus. J. Virol. 83: 4216-4226 [Abstract] [Full Text]  


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