Identification of residues in an orthopoxvirus interleukin-18 binding protein involved in ligand binding and species specificity

Interleukin-18 (IL-18) is a critical cytokine in inflammation and adaptive immune responses. The IL-18 binding proteins (IL-18BP) are a family of proteins that bind to, and inhibit the activity of, IL-18. Using point mutagenesis, we analyzed the ectromelia virus IL-18BP to identify residues involved in binding. Because p13 can bind both human and murine IL-18, and because it is highly homologous to the variola virus IL-18BP, we set out to identify residues that maybe involved in species specificity. Several of the mutations resulted incomplete abrogation of binding affinity. Three (F49A, E77A, and E69A) significantly affected binding with both species of IL- 18, but not to the same extent. Mutant H70A showed reduced affinity for human IL-18 while binding to marine IL-18 was not affected. This study demonstrated that interaction of IL- 18 with p 13 was similar to other IL-18BPs, however, novel species-specific interactions were identified. (C) 2004 Elsevier Inc. All rights reserved.