Foot-and-Mouth Disease Virus Receptors: Comparison of Bovine α(V) Integrin Utilization by Type A and O Viruses

Three members of the α(V) integrin family of cellular receptors, α(V)β(1), α(V)β(3), and α(V)β(6), have been identified as receptors for foot-and-mouth disease virus (FMDV) in vitro. The virus interacts with these receptors via a highly conserved arginine-glycine-aspartic acid (RGD) amino acid sequence motif located within the βG-βH (G-H) loop of VP1. Other α(V) integrins, as well as several other integrins, recognize and bind to RGD motifs on their natural ligands and also may be candidate receptors for FMDV. To analyze the roles of the α(V) integrins from a susceptible species as viral receptors, we molecularly cloned the bovine β(1), β(5), and β(6) integrin subunits. Using these subunits, along with previously cloned bovine α(V) and β(3) subunits, in a transient expression assay system, we compared the efficiencies of infection mediated by α(V)β(1), α(V)β(3), α(V)β(5), and α(V)β(6) among three strains of FMDV serotype A and two strains of serotype O. While all the viruses could infect cells expressing these integrins, they exhibited different efficiencies of integrin utilization. All the type A viruses used α(V)β(3) and α(V)β(6) with relatively high efficiency, while only one virus utilized α(V)β(1) with moderate efficiency. In contrast, both type O viruses utilized α(V)β(6) and α(V)β(1) with higher efficiency than α(V)β(3). Only low levels of viral replication were detected in α(V)β(5)-expressing cells infected with either serotype. Experiments in which the ligand-binding domains among the β subunits were exchanged indicated that this region of the integrin subunit appears to contribute to the differences in integrin utilizations among strains. In contrast, the G-H loops of the different viruses do not appear to be involved in this phenomenon. Thus, the ability of the virus to utilize multiple integrins in vitro may be a reflection of the use of multiple receptors during the course of infection within the susceptible host.