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Journal of Virology, March 2008, p. 2699-2704, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.02344-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inhibition of IRF-3 Activation by VP35 Is Critical for the High Level of Virulence of Ebola Virus{triangledown}

Amy L. Hartman,1 Brian H. Bird,3 Jonathan S. Towner,1 Zoi-Anna Antoniadou,2 Sherif R. Zaki,2 and Stuart T. Nichol1*

Special Pathogens Branch,1 Infectious Disease Pathology Branch, Division of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, 30329,2 University of California, Davis, School of Veterinary Medicine, Davis, California 956163

Received 30 October 2007/ Accepted 21 December 2007

Zaire ebolavirus causes a rapidly progressing hemorrhagic disease with high mortality. Identification of the viral virulence factors that contribute to the severity of disease induced by Ebola virus is critical for the design of therapeutics and vaccines against the disease. Given the rapidity of disease progression, virus interaction with the innate immune system early in the course of infection likely plays an important role in determining the outcome of the disease. The Ebola virus VP35 protein inhibits the activation of IRF-3, a critical transcription factor for the induction of early antiviral immunity. Previous studies revealed that a single amino acid change (R312A) in VP35 renders the protein unable to inhibit IRF-3 activation. A reverse-genetics-generated, mouse-adapted, recombinant Ebola virus that encodes the R312A mutation in VP35 was produced. We found that relative to the case for wild-type virus containing the authentic VP35 sequence, this single amino acid change in VP35 renders the virus completely attenuated in mice. Given that these viruses differ by only a single amino acid in the IRF-3 inhibitory domain of VP35, the level of alteration of virulence is remarkable and highlights the importance of VP35 for the pathogenesis of Ebola virus.

* Corresponding author. Mailing address: Centers for Disease Control and Prevention, 1600 Clifton Rd., MS G-14, Atlanta, GA 30329. Phone: (404) 639-1122. Fax: (404) 639-1118. E-mail: stn1{at}cdc.gov

{triangledown} Published ahead of print on 16 January 2008.

Journal of Virology, March 2008, p. 2699-2704, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.02344-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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