title: Ectromelia, vaccinia and cowpox viruses encode secreted interleukin-18-binding proteins.
abstract: Interleukin-18 (IL-18) is a proinflammatory cytokine that plays a key role in the activation of natural killer and T helper 1 cell responses principally by inducing interferon-gamma (IFN-gamma). Human and mouse secreted IL-18-binding proteins (IL-18BPs) have recently been described which block IL-18 activity but have no sequence similarity to membrane IL-18 receptors. Several poxvirus genes encode proteins with sequence similarity to IL-18BPs. Here we show that vaccinia, ectromelia and cowpox viruses secrete from infected cells a soluble IL-18BP (vIL-18BP) that may modulate the host antiviral response. The ectromelia virus protein was found to block NF-kappaB activation and induction of IFN-gamma in response to IL-18. The highly attenuated vaccinia virus modified virus Ankara encodes IL-18-binding activity, and thus deletion of the vIL-18BP may improve further the safety and immunogenicity of this promising human vaccine candidate. We confirm that molluscum contagiosum virus, a molluscipoxvirus that produces small skin tumours in immunocompetent individuals and opportunistic infections in immunodeficient AIDS patients, also encodes a related, larger vIL-18BP (gene MC54L). This protein may contribute to the lack of inflammatory response characteristic of molluscum contagiosum virus lesions. The expression of vIL-18BPs by distinct poxvirus genera that cause local or general viral dissemination, or persistent or acute infections in the host, emphasizes the importance of IL-18 in response to viral infections.
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: V P
authors.initials: VP
authors.lastname: Smith
authors.forename: N A
authors.initials: NA
authors.lastname: Bryant
authors.forename: A
authors.initials: A
authors.lastname: Alcamí
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D002460:Cell Line; D015608:Cowpox virus / Q000235:genetics / Q000378:metabolism; D003470:Culture Media; D004481:Ectromelia virus / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D008977:Molluscum contagiosum virus / Q000235:genetics / Q000378:metabolism; D018155:Orthopoxvirus / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism
chemical_list: D003470:Culture Media; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; C118370:interleukin-18 binding protein