High-Efficiency Utilization of the Bovine Integrin α v β 3 as a Receptor for Foot-and-Mouth Disease Virus Is Dependent on the Bovine β 3 Subunit

Abstract

We have previously reported that Foot-and-mouth disease virus (FMDV), which is virulent for cattle and swine, can utilize the integrin α v β 3 as a receptor on cultured cells. Since those studies were performed with the human integrin, we have molecularly cloned the bovine homolog of the integrin α v β 3 and have compared the two receptors for utilization by FMDV. Both the α v and β 3 subunits of the bovine integrin have high degrees of amino acid sequence similarity to their corresponding human subunits in the ectodomains (96%) and essentially identical transmembrane and cytoplasmic domains. Within the putative ligand-binding domains, the bovine and human α v subunits have a 98.8% amino acid sequence similarity while there is only a 93% similarity between the β 3 subunits of these two species. COS cell cultures, which are not susceptible to FMDV infection, become susceptible if cotransfected with α v and β 3 subunit cDNAs from a bovine or human source. Cultures cotransfected with the bovine α v β 3 subunit cDNAs and infected with FMDV synthesize greater amounts of viral proteins than do infected cultures cotransfected with the human integrin subunits. Cells cotransfected with a bovine α v subunit and a human β 3 subunit synthesize viral proteins at levels equivalent to those in cells expressing both human subunits. However, cells cotransfected with the human α v and the bovine β 3 subunits synthesize amounts of viral proteins equivalent to those in cells expressing both bovine subunits, indicating that the bovine β 3 subunit is responsible for the increased effectiveness of this receptor. By engineering chimeric bovine-human β 3 subunits, we have shown that this increase in receptor efficiency is due to sequences encoding the C-terminal one-third of the subunit ectodomain, which contains a highly structured cysteine-rich repeat region. We postulate that amino acid sequence differences within this region may be responsible for structural differences between the human and bovine β 3 subunit, leading to more efficient utilization of the bovine receptor by this bovine pathogen.