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Title: Sheeppox virus kelch-like gene SPPV-019 affects virus virulence

Author
item BALINSKY, C - UNIVERSITY OF CONNECTICUT
item DELHON, G - UNIVERSITY OF ILLINOIS
item Afonso, Claudio
item RISATTI, G - UNIVERSITY OF CONNECTICUT
item Borca, Manuel
item FRENCH, R - UNIVERSITY OF CONNECTICUT
item TULMAN, E - UNIVERSITY OF CONNECTICUT
item GEARY, S - UNIVERSITY OF CONNECTICUT
item ROCK, D - UNIVERSITY OF ILLINOIS

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/30/2007
Publication Date: 10/30/2007
Citation: Balinsky, C.A., Delhon, G., Afonso, C.L., Risatti, G.R., Borca, M.V., French, R.A., Tulman, E.R., Geary, S.J., Rock, D.L. 2007. Sheeppox virus kelch-like gene SPPV-019 affects virus virulence. Journal of Virology. 81(20):11392-11401.

Interpretive Summary: Sheeppox virus (SPPV) causes a highly significant disease of sheep and is the model virus to study poxviruses of the genus Capripoxvirus, that include goatpox virus (GTPV) and lumpy skin disease virus (LSDV), which cause disease in goats and cattle, respectively. Due to their significant economic impact and potential for disease transmission, CaPV diseases are listed diseases by the World Organization for Animal Health (OIE). Among the genes affected in vaccine strains of CaPV were those with products similar to kelch-like proteins encoded by eukaryotes and other poxviruses. Kelch-like proteins are encoded by members of chordopoxviral genera Orthopoxvirus, Capripoxvirus, Leporipoxvirus, Suipoxvirus, and Yatapoxvirus, and by 15 unassigned deerpox viruses. Kelch-like genes have been shown to affect lesion size, inflammatory cell infiltration, or virulence suggesting a role for kelch-like genes in poxvirus virulence and host-range, perhaps through modulation of inflammatory responses. In this study, we examined the role of a kelch-like protein in sheep, the natural SPPV host. Our data indicate that sheeppox kelch-like genes markedly affects SPPV virulence following intranasal or intradermal virus inoculation and suggest that manipulation of this gene can be used for the rational design of live attenuated vaccine viruses.

Technical Abstract: Sheeppox virus (SPPV), a member of the Capripoxvirus genus of the Poxviridae, is the etiologic agent of a significant disease of sheep in the developing world. Genomic analysis of pathogenic and vaccine capripoxviruses identified genes with potential roles in virulence and host-range, including three genes with similarity to kelch-like genes of other poxviruses and eukaryotes. Here, a mutant SPPV with a deletion in the SPPV-019 kelch-like gene, KLP, was derived from the pathogenic strain SPPV-SA. KLP exhibited in vitro growth characteristics similar to those of SPPV-SA and revertant virus (RvKLP). KLP-infected cells exhibited a reduction in Ca++-independent cell adhesion, suggesting that SPPV-019 may modulate cellular adhesion. When inoculated in sheep by intranasal or intradermal routes, KLP was markedly attenuated, as all KLP-infected lambs survived infection. In contrast, SPPV-SA and RvKLP induced mortality approaching 100%. Lambs inoculated with KLP exhibited marked reduction or delay in fever response, gross lesions, viremia, and virus shedding compared with parental and 15 revertant viruses. Together, these findings indicate that SPPV-019 is a significant SPPV.