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Journal of Virology, June 2009, p. 6247-6256, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.02460-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Dominant-Negative Mutant of rab5 Inhibits Infection of Cells by Foot-and-Mouth Disease Virus: Implications for Virus Entry{triangledown}

Helen L. Johns,1,{dagger} Stephen Berryman,1 Paul Monaghan,1 Graham J. Belsham,1,2 and Terry Jackson1*

Division of Microbiology, Institute for Animal Health, Pirbright, Surrey GU24 0NF, United Kingdom,1 National Veterinary Institute, Technical University of Denmark, Lindholm, 4771 Kalvehave, Denmark2

Received 1 December 2008/ Accepted 25 March 2009

Foot-and-mouth disease virus (FMDV) can use a number of different integrins ({alpha}vβ1, {alpha}vβ3, {alpha}vβ6, and {alpha}vβ8) as receptors to initiate infection. Infection mediated by {alpha}vβ6 is known to occur by clathrin-mediated endocytosis and is dependent on the acidic pH within endosomes. On internalization, virus is detected rapidly in early endosomes (EE) and subsequently in perinuclear recycling endosomes (PNRE), but not in late endosomal compartments. Due to the extreme sensitivity of FMDV to acidic pH, it is thought that EE can provide a pH low enough for infection to occur; however, definitive proof that infection takes place from within these compartments is still lacking. Here we have investigated the intracellular transport steps required for FMDV infection of IBRS-2 cells, which express {alpha}vβ8 as their FMDV receptor. These experiments confirmed that FMDV infection mediated by {alpha}vβ8 is also dependent on clathrin-mediate endocytosis and an acidic pH within endosomes. Also, the effect on FMDV infection of dominant-negative (DN) mutants of cellular rab proteins that regulate endosomal traffic was examined. Expression of DN rab5 reduced the number of FMDV-infected cells by 80%, while expression of DN rab4 or DN rab7 had virtually no effect on infection. Expression of DN rab11 inhibited infection by FMDV, albeit to a small extent (~35%). These results demonstrate that FMDV infection takes place predominantly from within EE and does not require virus trafficking to the late endosomal compartments. However, our results suggest that infection may not be exclusive to EE and that a small amount of infection could occur from within PNRE.

* Corresponding author. Mailing address: Pirbright Laboratory, Institute for Animal Health, Ash Road, Pirbright, Surrey GU24 0NF, United Kingdom. Phone: 44-01483-232441. Fax: 44-01483-232448. E-mail: terry.jackson{at}bbsrc.ac.uk

{triangledown} Published ahead of print on 8 April 2009.

{dagger} Present address: Veterinary Laboratories Agency, New Haw, Addlestone, Surrey KT15 3NB, United Kingdom.

Journal of Virology, June 2009, p. 6247-6256, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.02460-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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