Both carboxy- and amino-terminal domains of the vaccinia virus interferon resistance gene, E3L, are required for pathogenesis in a mouse model

The vaccinia virus (VV) E3L gene is responsible for providing interferon (I FN) resistance and a broad host range to VV in cell culture. The E3L gene p roduct contains two distinct domains. A conserved carboxy-terminal domain, which is required for the IFN resistance and broad host range of the virus, has been shown to bind double-stranded RNA (dsRNA) and inhibit the antivir al dsRNA-dependent protein kinase, PKR. The aminoterminal domain, while con served among orthopoxviruses, is dispensable in cell culture. To study the role of E3L in whole-animal infections, WR strain VV recombinants either la cking E3L (VV Delta E3L) or expressing an amino-terminal (VVE3L Delta 83N) or carboxy-terminal (VVE3L Delta 26C) truncation of E3L were constructed. W hereas wild-type VV had a 50% lethal dose of approximately 10(4) PFU after intranasal infection, and elicited severe weight loss and morbidity, VV Del ta E3L was apathogenic, leading to no death, weight loss, or morbidity. VV Delta E3L was also apathogenic after intracranial injection. Although the a mino-terminal domain of E3L is dispensable for infection of cells in cultur e, both the amino- and carboxy-terminal domains of E3L were required for fu ll pathogenesis in intranasal infections. These results demonstrate that th e entire E3L gene is required for pathogenesis in the mouse model.