SERP1, A SERINE PROTEINASE-INHIBITOR ENCODED BY MYXOMA VIRUS, IS A SECRETED GLYCOPROTEIN THAT INTERFERES WITH INFLAMMATION

Myxoma virus is a leporipoxvirus that causes a rapidly lethal, generalized infection known as myxomatosis in the European rabbit (Oryctolagus cuniculus). A characteristic feature of myxomatosis is the specific downregulation of key pathways important for numerous host defenses against the viral infection. The SERP1 gene has significant sequence similarity to the serpin superfamily of serine proteinase inhibitors and is one of many virulence factor genes located within the terminal regions of the myxoma virus genome. Transcriptional analysis of the SERP1 gene in myxoma virus (strain Lausanne) indicates that it is expressed as a late gene and studies using a polyclonal anti-SERP1 antiserum indicate that it encodes a secreted protein with an apparent molecular weight of 55 kDa. Using myxoma virus and recombinant vaccinia virus constructs for experiments with tunicamycin and peptide N-glycosidase F, it is shown that the secreted SERP1 protein is modified by N-linked glycosylation. Mutation of both copies of the SERP1 gene in myxoma virus results in a significant attenuation of the virus, such that more than 50% of infected animals are able to recover from the otherwise lethal infection. Histological analyses of lesions taken from infected animals suggest that in the absence of the SERP1 protein, a more effective inflammatory response occurs, allowing a more rapid resolution of the infection. This suggests that SERP1 contributes to viral pathogenesis by interacting with cellular component(s) involved in the regulation of inflammation. © 1993 Academic Press. All rights reserved.