Major amino acid sequence variants of viral vascular endothelial growth factor are functionally equivalent during Orf virus infection of sheep skin

Orf virus infection causes a contagious pustular dermatitis characterized by extensive vascular changes that have been linked to a virally encoded vascular endothelial growth factor (VEGF). The VEGF genes of different strains of orf virus can vary extensively in amino acid sequence. Functional analyses of two major variant VEGF proteins derived from orf virus strains, NZ2 and NZ7, have revealed quantitative differences in biological activities and receptor binding specificities suggesting that these viral VEGFs could have different roles in the pathology of orf virus infection. In this study, we show that both orf virus strains express equivalent levels of the viral VEGF variants and during infection of sheep skin induce comparable levels of vascularization, edema, epidermal rete ridge and scab formation. Recombinants of orf virus NZ2 and NZ7 strains in which the variant VEGF genes were disrupted showed markedly reduced vascular changes and evidence of partially attenuated viral growth. These results demonstrate that despite substantial differences in sequence and biological activity in vitro, these virally expressed virulence factors are functionally equivalent in their natural host, contributing equally to orf virus pathology.