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Journal of Virology, September 2009, p. 9223-9236, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00861-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cowpox Virus Expresses a Novel Ankyrin Repeat NF-{kappa}B Inhibitor That Controls Inflammatory Cell Influx into Virus-Infected Tissues and Is Critical for Virus Pathogenesis{triangledown}

Mohamed Ragaa Mohamed, Masmudur M. Rahman, Amanda Rice, Richard W. Moyer, Steven J. Werden, and Grant McFadden*

Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610

Received 28 April 2009/ Accepted 19 June 2009

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.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610. Phone: (352) 273-6852. Fax: (352) 273-6849. E-mail: grantmcf{at}ufl.edu

{triangledown} Published ahead of print on 1 July 2009.

Journal of Virology, September 2009, p. 9223-9236, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00861-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Werden, S. J., Lanchbury, J., Shattuck, D., Neff, C., Dufford, M., McFadden, G. (2009). The Myxoma Virus M-T5 Ankyrin Repeat Host Range Protein Is a Novel Adaptor That Coordinately Links the Cellular Signaling Pathways Mediated by Akt and Skp1 in Virus-Infected Cells. J. Virol. 83: 12068-12083 [Abstract] [Full Text]  


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