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Journal of Virology, July 2005, p. 8506-8518, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8506-8518.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Analysis of Foot-and-Mouth Disease Virus Internalization Events in Cultured Cells

Vivian O'Donnell,1,2 Michael LaRocco,2 Hernando Duque,3 and Barry Baxt2*

Department of Pathobiology and Veterinary Science, University of Connecticut at Storrs, Storrs, Connecticut 06269,1 Foreign Animal Disease Research Unit, United States Department of Agriculture, Agricultural Research Service, Plum Island Animal Disease Center, Greenport, NY 11944,2 United States Department of Agriculture, Animal Plant Health Inspection Service, Veterinary Services, Foreign Animal Disease Diagnostic Laboratory, Greenport, NY 119443

Received 12 November 2004/ Accepted 7 March 2005

It has been demonstrated that foot-and-mouth disease virus (FMDV) can utilize at least four members of the {alpha}V subgroup of the integrin family of receptors in vitro. The virus interacts with these receptors via a highly conserved arginine-glycine-aspartic acid amino acid sequence motif located within the ßG-ßH loop of VP1. While there have been extensive studies of virus-receptor interactions at the cell surface, our understanding of the events during viral entry into the infected cell is still not clear. We have utilized confocal microscopy to analyze the entry of two FMDV serotypes (types A and O) after interaction with integrin receptors at the cell surface. In cell cultures expressing both the {alpha}Vß3 and {alpha}Vß6 integrins, virus adsorbed to the cells at 4°C appears to colocalize almost exclusively with the {alpha}Vß6 integrin. Upon shifting the infected cells to 37°C, FMDV capsid proteins were detected within 15 min after the temperature shift, in association with the integrin in vesicular structures that were positive for a marker of clathrin-mediated endocytosis. In contrast, virus did not colocalize with a marker for caveola-mediated endocytosis. Virus remained associated with the integrin until about 1 h after the temperature shift, when viral proteins appeared around the perinuclear region of the cell. By 15 min after the temperature shift, viral proteins were seen colocalizing with a marker for early endosomes, while no colocalization with late endosomal markers was observed. In the presence of monensin, which raises the pH of endocytic vesicles and has been shown to inhibit FMDV replication, viral proteins were not released from the recycling endosome structures. Viral proteins were not observed associated with the endoplasmic reticulum or the Golgi. These data indicate that FMDV utilizes the clathrin-mediated endocytosis pathway to infect the cells and that viral replication begins due to acidification of endocytic vesicles, causing the breakdown of the viral capsid structure and release of the genome by an as-yet-unidentified mechanism.

* Corresponding author. Mailing address: USDA, ARS, Plum Island Animal Disease Center, PO Box 848, Greenport, NY 11944-0848. Phone: (631) 323-3354. Fax: (631) 323-3006. E-mail: bbaxt{at}piadc.ars.usda.gov.

Journal of Virology, July 2005, p. 8506-8518, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8506-8518.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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