Journal
JOURNAL OF VIROLOGY
Volume 83, Issue 18, Pages 9223-9236Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00861-09
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Funding
- University of Florida College of Medicine
- Southeast Regional Center of Excellence for Emerging Infections and Biodefense
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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-kappa B1/p105 and inhibit the NF-kappa B signaling pathway. Here, we present the in vitro and in vivo characterization of the targeted gene knockout of this novel NF-kappa B inhibitor in CPXV. Our results demonstrate that the vCpx-006KO uniquely induces a variety of NF-kappa B-controlled proinflammatory cytokines from infected myeloid cells, accompanied by a rapid phosphorylation of the I kappa B kinase complex and subsequent degradation of the NF-kappa B cellular inhibitors I kappa B alpha and NF-kappa B1/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-kappa B signaling pathway at tissue sites of virus replication in situ.
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