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Title: THE ROUTE OF ENTRY OF FOOT-AND-MOUTH DISEASE VIRUS INTO CULTURED CELLS IS RECEPTOR-DEPENDENT

Author
item O'DONNELL, VIVIAN - UNIV. OF CONN
item Baxt, Barry

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 5/1/2005
Publication Date: 6/19/2005
Citation: O'Donnell, V., Baxt, B. 2005. The Route of Entry of Foot-and-Mouth Disease Virus into Cultured Cells is Receptor-dependent. XIIIth Meeting of the European Study Group for the Molecular Biology of Picornaviruses. p B04.

Interpretive Summary:

Technical Abstract: Foot-and-mouth disease virus (FMDV) utilizes a number of 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 loss of viral virulence in the animal accompanied by the loss in ability to use integrins as receptors. These avirulent viral variants acquire positively charged amino acids on surface-exposed structural proteins and now utilize cell surface heparan sulfate (HS) as a receptor. 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. However, it has been suggested that HS internalizes its bound ligands by a caveolae-mediated mechanism. To analyze the entry of FMDV by cell-surface HS, we utilized a genetically engineered variant of type O1Campos (O1C3056R) which can only utilize HS as a receptor, and followed viral entry using confocal microscopy. After binding virus cells at 4 degrees C followed by shifting the temperature to 37 degrees C, virus colocalized with caveolin-1, a marker for cellular caveolae. In contrast, integrin-binding viruses only colocalized with clathrin. Chlorpromazine, a compound which inhibits the formation of clathrin-coated pits, did not inhibit the replication of O1C3056R but did inhibit integrin-binding O1Campos replication, confirming that O1C3056R was not using a clathrin-mediated mechanism. Surprisingly, nystatin, a compound which inhibits the formation of lipid rafts and depletes cellular cholesterol, did not inhibit the replication of O1C3056R, while monensin, an agent which raises the pH of early endosomes did inhibit viral replication. These results suggest that this viral variant, while colocalizing with caveolin-1, does not appear to utilize the “classical” caveolae-mediated entry route, 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.