CrmE, a novel soluble tumor necrosis factor receptor encoded by poxviruses

Cytokines and chemokines play a critical role in both the innate and acquir ed immune responses and constitute prime targets for pathogen sabotage. Mol ecular mimicry of cytokines and cytokine receptors is a mechanism encoded b y large DNA viruses to modulate the host immune response. Three tumor necro sis factor receptors (TNFRs) have been identified in the poxvirus cowpox vi rus, Here we report the identification and characterization of a fourth dis tinct soluble TNFR, named cytokine response modifier E (CrmE), encoded by c owpox virus. The crmE gene has been sequenced in strains of the orthopoxvir uses cowpox virus, ectromelia virus, and camelpox virus, and was found to b e active in cowpox virus. crmE is expressed as a secreted 18-kDa protein wi th TNF binding activity. CrmE was produced in the baculovirus and vaccinia virus expression systems and was shown to bind human, mouse, and rat TNF, b ut not human lymphotoxin alpha, conjugates of lymphotoxins alpha and beta, or seven other ligands of the TNF superfamily, However, CrmE protects cells only from the cytolytic activity of human TNF. CrmE is a new member of the TNFR superfamily which is expressed as a soluble molecule that blocks the binding of TNF to high-affinity TNFRs on the cell surface, The remarkable f inding of a fourth poxvirus-encoded TNFR suggests that modulation of TNF ac tivity is complex and represents a novel viral immune evasion mechanism.