Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 1, 2001
Publication Date: February 20, 2003
Citation: DUQUE, H., BAXT, B. FOOT-AND-MOUTH DISEASE VIRUS RECEPTORS: COMPARISON OF BOVINE ALPHAV INTEGRIN UTILIZATION BY TYPES A AND O VIRUSES. JOURNAL OF VIROLOGY. 77:2500-2511, 2003. Interpretive Summary: Foot-and-mouth disease (FMD) is a highly infectious disease of economically important cloven-hoofed livestock. The disease is caused by the foot-and- mouth disease virus (FMDV) and causes food supply and economic disruption to countries that are afflicted by it. In order for the virus to cause disease, it must first be able to infect cells of susceptible species. The first step in infection is the binding of the virus to molecules on the surface of susceptible cells, called receptors. We have previously identified the receptor for FMDV as member of a large class of cellular receptors, called integrins. Integrins are important receptors and play a role in how cells interact with each other and with their environment in an organism. They are comprised of two protein chains, called alpha and beta, and have been found in every animal species where they have been looked for. Three integrins have been identified as FMDV receptors, alphaVbeta1. alphaVbeta3 and alphaVbeta6. In order to analyze the roles these multiple receptors play in enabling the virus to cause disease, we have molecularly cloned the beta1, beta5, and beta6 subunits from bovines. We compared the ability of each of these receptors to cause infection using a lab-strain and field strain virus. We found that the field strain virus, which is highly infectious in bovines, utilizes the four different receptors with greater efficiency than the lab-strain virus. This ability to use different receptors may influence the relative infectious nature of the isolate in susceptible species and may have implications which may be useful in designing anti-viral strategies based on receptor blockade.
Technical Abstract: Several members of the alphaV integrin family of cellular receptors, namely alphaVbeta3, alphaVbeta6, and alphaVbeta1, have been identified as receptor for foot-and-mouth disease virus (FMDV) in culture cells. The site on the virus that interacts with these receptors is a highly conserved arginine- glycine-aspartic acid (RGD) amino acid sequence motif located within the betaG-betaH loop of VP1. All of the alphaV integrins, as well as several others, recognize and bind to RGD motifs on their natural ligands and thus be candidate receptors for FMDV. To analyze the roles of alphaV integrins a viral receptors from a host species, we molecularly cloned the bovine beta1 beta5 and beta6 integrin subunits. Using an integrin transient expression assay in COS-1 cells, we compared the efficiency of infection mediated by these different integrins between two FMDV strains, a type A12 lab-strain virus, and a highly bovine-virulent derivative of a type O1Campos. While both strains could infect cells expressing bovine alphaVbeta1, alphaVbeta3 alphaVbeta5, and alphaVbeta6, they surprisingly exhibited different efficiencies of integrin utilization. Type A12 used the alphaVbeta6 and alphaVbeta3 with relatively high efficiency and poorly utilized alphaVbeta1 and alphaVbeta5. In contrast type O1Campos utilized alphaVbeta6 most efficiently and used alphaVbeta1, alphaVbeta3 to a lesser, but equal degree As with type A12, type O1Campos utilized alphaVbeta5 poorly. These results suggest that while FMDV can utilize several integrins as receptors in vitro different virus isolates appear to exhibit altered affinities for different integrins. These differences may influence the relative virulence of these isolates in susceptible species in vivo.