Sequence and Functional Analysis of a Homolog of Interleukin-10 Encoded by the Parapoxvirus Orf Virus

Abstract

Orf virus is a large DNA virus and is the type species of the Parapoxvirus genus of the family Poxviridae. Orf virus infects the epithelium of sheep and goats and is transmissible to humans. Recently we discovered a gene in orf virus that encodes a polypeptide with remarkable homology to mammalian interleukin (IL-10) and viral encoded IL-10s of herpes viruses. The predicted polypeptide sequence shows high levels of amino acid identity to IL-10 of sheep (80%), cattle (75%), humans (67%) and mice (64%), as well as IL-10-like proteins of Epstein-Barr virus (63%) and equine herpes virus (67%). The C-terminal region, comprising two-thirds of the orf virus protein, is identical to ovine IL-10 which suggests that this gene has been captured from its host sheep during the evolution of orf virus. In contrast the N-terminal region shows little homology with cellular IL10s and in this respect resembles other viral IL-10s. IL-10 is a pleiotrophic cytokine that can exert either immunostimulatory or immunosuppressive effects on many cell types. IL-10 is a potent anti-inflammatory cytokine with inhibitory effects on non-specific immunity in particular macrophage function and Thl effector function. Our studies so far, indicate, that the functional activities of orf virus IL-10 are the same as ovine IL-10. Orf virus IL-10 stimulates mouse thymocyte proliferation and inhibits cytokine synthesis in lipopolysaccharide-activated ovine macrophages, peripheral blood monocytes and keratinocytes. Infection of sheep with an IL-10 deletion mutant of orf virus has shown that interferon-gamma levels are higher in tissue infected with the mutant virus than the parent virus. The functional activities of IL-10 and our data on orf virus IL-10 suggest a role in immune evasion.

The role of interleukin 10 in the pathogenesis and potential treatment of skin diseases

“…The apparent mechanism of OV in preventing the accumulation and activation of CD8ϩ T cells is consistent with the effects of IL-10 on cellular immunity. 78,79 The orf virus is unusual in that it may reinfect a host multiple times, suggesting impaired host formation of immunologic memory. A recent in vitro study indicated that ovIL-10 impairs maturation of bone marrow-derived dendritic cells and spontaneous migration of LCs from the epidermis.…”

Pathogenesis in lambs and sequence analysis of putative virulence genes of Brazilian orf virus isolates

“…In any case, the VEGF changes alone certainly do not explain the attenuated phenotype of isolate SV581/11. Isolate SV581/11 (and SV252/11) also presented unusual mutations in the IL-10v gene product, a viral protein homologous to ovine IL-10 that acts reducing the inflammatory response (Fleming et al, 1997). IL-10v has been shown to be an ORFV virulence factor and its removal has partial effects on ORFV virulence .…”

Interleukin-10 Superfamily and Cancer

“…All the monomers of the IL-10 superfamily are topologically similar to the single chain of IL-10; however, slight differences in their molecular structure cause a wide variety of biological effects of these cytokines (Zdanov, 2010). Interestingly, numerous viral homologs of IL-10 are known, including human and simian cytomegalovirus Lockridge et al, 2000), equine type 2 herpes virus (Rode et al, 1993), Epstein-Barr virus (Hsu et al, 1990;Vieira et al, 1991), and Orf parapoxvirus (Fleming et al, 1997(Fleming et al, , 2000. Notably, all the representatives of the IL-10 superfamily are regarded as class II cytokines, which means that they have structural characteristics similar to those of type I and II IFNs (Pestka et al, 2004b;Pestka, 2005, 2007;Dunn et al, 2006;Zdanov, 2010).…”