Analysis of Foot-and-Mouth Disease Virus Integrin Receptor Expression in Tissues from Na € ıve and Infected Cattle V. O’Donnell *,† , J. M. Pacheco * , D. Gregg * and B. Baxt * * United States Department of Agriculture, Agricultural Research Service, Plum Island Animal Disease Center, Greenport, NY and † Department of Pathobiology and Veterinary Sciences, University of Connecticut, Storrs, CT 11944, USA Summary Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals principally affect- ing cattle, pigs and sheep. FMD virus (FMDV) uses the a V b 1 , a V b 3 , a V b 6 , and a V b 8 integrins as receptors in vitro via a highly conserved arginineeglycineeaspartic acid amino acid sequence motif located within the bG-bH loop of VP1. Immunofluorescence and confocal microscopy were used to study the expression of two major FMDV receptors, a V b 3 and a V b 6 , within epithelial tissues from FMDV-infected and uninfected cattle in order to understand the role of these receptors in tissue tropism. Integrin a V b 6 was expressed by epithelial cells in tissues that are important sites for FMDV replication (i.e. tongue and coronary band). Integrin a V b 3 was detected in epithelium of all tissues examined except tongue. In addition, a V b 3 expression was associated with blood vessels in all tissues examined. In infected tissues, a V b 6 integrin was distributed on the surface of those epithelial cells also expressing FMDV antigen. Although integrin a V b 3 has been shown to be a receptor for FMDV, no expression of a V b 3 was associated with FMDV-positive keratinocytes in the tongue. In contrast, podal epithelial cells containing FMDV antigen also expressed a V b 3 integrin. Thus, at the cellular level the expression of these two integrins correlates with susceptibility to infection and may contribute substantially to viral tropism in FMD pathogenesis. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: cattle; foot-and-mouth disease virus; integrin; receptor Introduction Foot-and-mouth disease (FMD) is a highly conta- gious viral disease of cloven-hoofed animals, princi- pally affecting cattle, pigs and sheep. The causative agent, FMD virus (FMDV), is the type species of the Aphthovirus genus of the family Picornaviridae. Following infection with FMDV, one of the most prominent characteristics of the disease is the forma- tion of vesicles in the stratum spinosum of the epithe- lium of the tongue, the coronary band and the interdigital cleft of the foot (Frenkel, 1949, 1950). De- spite extensive studies, the basis for the viral tropism to these sites remains unclear. It is well established that FMDV initiates infection in vitro by binding to any of the four members of the a V subgroup of the integrin family of cellular receptors (a V b 1 , a V b 3 , a V b 6 and a V b 8 ) via a highly conserved arginineeglycineeaspartic acid (RGD) amino acid sequence motif located within the bG-bH loop of VP1 (Berinstein et al., 1995; Neff et al., 1998; Jackson et al., 2000, 2002, 2004; Duque and Baxt, 2003). We have recently shown that the a V b 6 integrin acts as a high-affinity receptor for the virus, while a V b 3 inter- acts with the virus with a much lower affinity (Duque et al., 2004). In addition, FMDV serotype A viruses utilize both the a V b 3 and a V b 6 integrins as receptors in cultured cells, while serotype O viruses have a higher affinity for the a V b 6 integrin (Duque and Baxt, 2003). In addition to cellular integrins, FMDV is also able to utilize alternative membrane molecules as receptors (Mason et al., 1993; Jackson Correspondence to: V. O’Donnell (e-mail: vivian.odonnell@ars.usda. gov). 0021-9975/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jcpa.2008.09.008 J. Comp. Path. 2009, Vol. 141, 98e112 Available online at www.sciencedirect.com www.elsevier.com/locate/jcpa