Journal of Virology, January 2001, p. 226-233, Vol. 75, No. 1
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.1.226-233.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom
Received 2 August 2000/Accepted 29 September 2000
Cytokines and chemokines play a critical role in both the innate
and acquired immune responses and constitute prime targets for pathogen
sabotage. Molecular mimicry of cytokines and cytokine receptors is a
mechanism encoded by large DNA viruses to modulate the host immune
response. Three tumor necrosis factor receptors (TNFRs) have been
identified in the poxvirus cowpox virus. Here we report the
identification and characterization of a fourth distinct soluble TNFR,
named cytokine response modifier E (CrmE), encoded by cowpox virus. The
crmE gene has been sequenced in strains of the
orthopoxviruses cowpox virus, ectromelia virus, and camelpox virus, and
was found to be active in cowpox virus. crmE is expressed as a secreted 18-kDa protein with TNF binding activity. CrmE was produced in the baculovirus and vaccinia virus expression systems and
was shown to bind human, mouse, and rat TNF, but not human lymphotoxin
, conjugates of lymphotoxins
and
, 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 finding of a fourth poxvirus-encoded TNFR suggests that
modulation of TNF activity is complex and represents a novel viral
immune evasion mechanism.
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