Modified vaccinia virus Ankara can activate NF-kappaB transcription factors through a double-stranded RNA-activated protein kinase (PKR)-dependent pathway during the early phase of virus replication.
Modified vaccinia virus Ankara (MVA), which is a promising replication-defective vaccine vector, is unusual among the orthopoxviruses in activating NF-kappaB transcription factors in cells of several types. In human embryonic kidney (HEK 293T) cells, the MVA-induced depletion of IkappaBalpha required to activate NF-kappaB is inhibited by UV-inactivation of the virus, and begins before viral DNA replication. In HEK 293T, CHO, or RK13 cells, expression of the cowpox virus CP77 early gene, or the vaccinia virus K1L early gene suppresses MVA-induced IkappaBalpha depletion. In mouse embryonic fibroblasts (MEFs), MVA induction of IkappaBalpha depletion is dependent on the expression of mouse or human double-stranded RNA-activated protein kinase (PKR). These results demonstrate that events during the early phase of MVA replication can induce PKR-mediated processes contributing both to the activation of NF-kappaB signaling, and to processes that may restrict viral replication. This property may contribute to the efficacy of this vaccine virus.
Lynch
Heather E
HE
Department of Molecular Genetics and Microbiology, Box 3020, Duke University Medical Center, Durham, NC 27710, USA. heather.lynch@duke.edu
Ray
Caroline A
CA
Oie
Katrina L
KL
Pollara
Justin J
JJ
Petty
Ian T D
IT
Sadler
Anthony J
AJ
Williams
Bryan R G
BR
Pickup
David J
DJ
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000096:biosynthesis*; D014616:Vaccinia virus / Q000276:immunology* / Q000502:physiology*; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000276:immunology*
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D019892:eIF-2 Kinase