title: Cowpox virus expresses a novel ankyrin repeat NF-kappaB inhibitor that controls inflammatory cell influx into virus-infected tissues and is critical for virus pathogenesis.
abstract: Many pathogenic orthopoxviruses like variola virus, monkeypox virus, and cowpox virus (CPXV), but not vaccinia virus, encode a unique family of ankyrin (ANK) repeat-containing proteins that interact directly with NF-kappaB1/p105 and inhibit the NF-kappaB signaling pathway. Here, we present the in vitro and in vivo characterization of the targeted gene knockout of this novel NF-kappaB inhibitor in CPXV. Our results demonstrate that the vCpx-006KO uniquely induces a variety of NF-kappaB-controlled proinflammatory cytokines from infected myeloid cells, accompanied by a rapid phosphorylation of the IkappaB kinase complex and subsequent degradation of the NF-kappaB cellular inhibitors IkappaBalpha and NF-kappaB1/p105. Moreover, the vCpx-006KO virus was attenuated for virulence in mice and induced a significantly elevated cellular inflammatory process at tissue sites of virus replication in the lung. These results indicate that members of this ANK repeat family are utilized specifically by pathogenic orthopoxviruses to repress the NF-kappaB signaling pathway at tissue sites of virus replication in situ.
authors: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, 32610, USA.
authors: Mohamed Ragaa
authors: MR
authors: Mohamed
authors: Masmudur M
authors: MM
authors: Rahman
authors: Amanda
authors: A
authors: Rice
authors: Richard W
authors: RW
authors: Moyer
authors: Steven J
authors: SJ
authors: Werden
authors: Grant
authors: G
authors: McFadden
mesh_terms: D000818:Animals; D017089:Ankyrin Repeat; D002465:Cell Movement / Q000276:immunology*; D015608:Cowpox virus / Q000737:chemistry / Q000472:pathogenicity*; D016207:Cytokines; D007249:Inflammation / Q000473:pathology*; D008171:Lung Diseases / Q000473:pathology / Q000821:virology; D051379:Mice; D022423:Myeloid Cells / Q000821:virology; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014764:Viral Proteins / Q000502:physiology*
chemical_list: D016207:Cytokines; D052002:NF-kappa B p50 Subunit; D014764:Viral Proteins