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Journal of Virology, June 2008, p. 5348-5358, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.00215-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Whole-Genome Expression Profiling Reveals That Inhibition of Host Innate Immune Response Pathways by Ebola Virus Can Be Reversed by a Single Amino Acid Change in the VP35 Protein{triangledown} ,{dagger}

Amy L. Hartman,1,{ddagger} Ling Ling,2 Stuart T. Nichol,1* and Martin L. Hibberd2

Centers for Disease Control and Prevention, Special Pathogens Branch, Atlanta, Georgia,1 Infectious Disease, Genome Institute of Singapore, Singapore, Singapore2

Received 30 January 2008/ Accepted 10 March 2008

Ebola hemorrhagic fever is a rapidly progressing acute febrile illness characterized by high virus replication, severe immunosuppression, and case fatalities of ca. 80%. Inhibition of phosphorylation of interferon regulatory factor 3 (IRF-3) by the Ebola VP35 protein may block the host innate immune response and play an important role in the severity of disease. We used two precisely defined reverse genetics-generated Ebola viruses to investigate global host cell responses resulting from the inhibition of IRF-3 phosphorylation. The two viruses encoded either wild-type (WT) VP35 protein (recEbo-VP35/WT) or VP35 with an arginine (R)-to-alanine (A) amino acid substitution at position 312 (recEbo-VP35/R312A) within a previously defined IRF-3 inhibitory domain. When sucrose-gradient purified virus was used for infection, host cell whole-genome expression profiling revealed striking differences in human liver cell responses to these viruses differing by a single amino acid. The inhibition of host innate immune responses by WT Ebola virus was so potent that little difference in interferon and antiviral gene expression could be discerned between cells infected with purified WT, inactivated virus, or mock-infected cells. However, infection with recEbo-VP35/R312A virus resulted in a strong innate immune response including increased expression of MDA-5, RIG-I, RANTES, MCP-1, ISG-15, ISG-54, ISG-56, ISG-60, STAT1, IRF-9, OAS, and Mx1. The clear gene expression differences were obscured if unpurified virus stocks were used to initiate infection, presumably due to soluble factors present in virus-infected cell supernatant preparations. Ebola virus VP35 protein clearly plays a pivotal role in the potent inhibition of the host innate immune responses, and the present study indicates that VP35 has a wider effect on host cell responses than previously shown. The ability to eliminate this inhibitory effect with a single amino acid change in VP35 demonstrates the critical role this protein must play in the severe aspects this highly fatal disease.

* 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 19 March 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} Present address: Center for Vaccine Research and the Department of Infectious Disease and Microbiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261.

Journal of Virology, June 2008, p. 5348-5358, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.00215-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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