title: Yaba monkey tumor virus encodes a functional inhibitor of interleukin-18.
abstract: Interleukin-18 (IL-18) is a critical proinflammatory cytokine whose extracellular bioactivity is regulated by a cellular IL-18 binding protein (IL-18BP). Many poxviruses have acquired variants of this IL-18BP gene, some of which have been shown to act as viral virulence factors. Yaba monkey tumor virus (YMTV) encodes a related family member, 14L, which is similar to the orthopoxvirus IL-18BPs. YMTV 14L was expressed from a baculovirus system and tested for its ability to bind and inhibit IL-18. We found that YMTV 14L bound both human IL-18 (hIL-18) and murine IL-18 with high affinity, at 4.1 nM and 6.5 nM, respectively. YMTV 14L was able to fully sequester hIL-18 but could only partially inhibit the biological activity of hIL-18 as measured by gamma interferon secretion from KG-1 cells. Additionally, 17 hIL-18 point mutants were tested by surface plasmon resonance for their ability to bind to YMTV 14L. Two clusters of hIL-18 surface residues were found to be important for the hIL-18-YMTV 14L interaction, in contrast to results for the Variola virus IL-18BP, which has been shown to primarily interact with a single cluster of three amino acids. The altered binding specificity of YMTV 14L most likely represents an adaptation resulting in increased fitness of the virus and affirms the plasticity of poxviral inhibitor domains that target cytokines like IL-18.
authors.affiliation: University of Florida, 1600 SW Archer Road, ARB Room R4-295, P.O. Box 100332, Gainesville, FL 32610, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Nazarian
authors.forename: Masmudur M
authors.initials: MM
authors.lastname: Rahman
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Werden
authors.forename: Danielle
authors.initials: D
authors.lastname: Villeneuve
authors.forename: Xiangzhi
authors.initials: X
authors.lastname: Meng
authors.forename: Craig
authors.initials: C
authors.lastname: Brunetti
authors.forename: Chalice
authors.initials: C
authors.lastname: Valeriano
authors.forename: Christina
authors.initials: C
authors.lastname: Wong
authors.forename: Rajkumari
authors.initials: R
authors.lastname: Singh
authors.forename: John W
authors.initials: JW
authors.lastname: Barrett
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiang
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
mesh_terms: D002460:Cell Line; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000037:antagonists & inhibitors*; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020349:Surface Plasmon Resonance; D014764:Viral Proteins / Q000502:physiology*; D014999:Yaba monkey tumor virus / Q000276:immunology*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D014764:Viral Proteins; C118370:interleukin-18 binding protein; D007371:Interferon-gamma