Abstract
The vaccinia virus (VACV) strain Western Reserve C16 protein has been characterized and its effects on virus replication and virulence have been determined. The C16L gene is present in the inverted terminal repeat and so is one of the few VACV genes that are diploid. The C16 protein is highly conserved between different VACV strains, and also in the orthopoxviruses variola virus, ectromelia virus, horsepox virus and cowpox virus. C16 is a 37.5 kDa protein, which is expressed early during infection and localizes to the cell nucleus and cytoplasm of infected and transfected cells. The loss of the C16L gene had no effect on virus growth kinetics but did reduce plaque size slightly. Furthermore, the virulence of a virus lacking C16L (vΔC16) was reduced in a murine intranasal model compared with control viruses and there were reduced virus titres from 4 days post-infection. In the absence of C16, the recruitment of inflammatory cells in the lung and bronchoalveolar lavage was increased early after infection (day 3) and more CD4+ and CD8+ T cells expressed the CD69 activation marker. Conversely, late after infection with vΔC16 (day 10) there were fewer T cells remaining, indicating more rapid clearance of infection. Collectively, these data indicate that C16 diminishes the immune response and is an intracellular immunomodulator.
Highlights
Vaccinia virus (VACV) is the prototypical member of the genus Orthopoxvirus (OPV) of the Poxviridae and is famous as the live vaccine used to eradicate smallpox, an extinct human disease caused by variola virus (VARV) (Fenner et al, 1988)
This sequence is critical for the ability of IL-1 receptor antagonist (IL-1ra) to antagonize signalling from the IL-1 receptor (IL-1R) and prompted the proposal that the VACV protein might act as a secreted viral IL-1ra and inhibit signalling from the IL-1R by receptor blockade (Kluczyk et al, 2004)
To study the function of the C16 protein, a VACV strain Western Reserve (WR) mutant lacking both copies of the C16L gene, vDC16, was constructed (Methods) from plaque-purified VACV WR
Summary
Vaccinia virus (VACV) is the prototypical member of the genus Orthopoxvirus (OPV) of the Poxviridae and is famous as the live vaccine used to eradicate smallpox, an extinct human disease caused by variola virus (VARV) (Fenner et al, 1988). There are highly conserved orthologues of C16 in several other OPVs, suggesting an important function, and bioinformatic analysis identified a conserved 6 aa sequence at the C terminus of C16 that is present in the same region of the IL-1 receptor antagonist (IL-1ra) protein (Kluczyk et al, 2002). This 6 aa sequence is conserved in the VACV strain Copenhagen orthologue of C16 (termed C10) (Goebel et al, 1990), and in orthologues in other OPVs (www.poxvirus.org). This sequence is critical for the ability of IL-1ra to antagonize signalling from the IL-1 receptor (IL-1R) and prompted the proposal that the VACV protein might act as a secreted viral IL-1ra and inhibit signalling from the IL-1R by receptor blockade (Kluczyk et al, 2004)
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