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Journal of Virology, November 2008, p. 10735-10746, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01305-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Vaccinia Virus Subverts a Mitochondrial Antiviral Signaling Protein-Dependent Innate Immune Response in Keratinocytes through Its Double-Stranded RNA Binding Protein, E3{triangledown}

Liang Deng,1* Peihong Dai,2 Tanvi Parikh,1,2 Hua Cao,1,2 Vijay Bhoj,4 Qinmiao Sun,4 Zhijian Chen,4 Taha Merghoub,3 Alan Houghton,3 and Stewart Shuman2*

Dermatology Service, Department of Medicine,1 Molecular Biology Program,2 Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021,3 Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 753904

Received 23 June 2008/ Accepted 7 August 2008

Skin keratinocytes provide a first line of defense against invading microorganisms in two ways: (i) by acting as a physical barrier to pathogen entry and (ii) by initiating a vigorous innate immune response upon sensing danger signals. How keratinocytes detect virus infections and generate antiviral immune responses is not well understood. Orthopoxviruses are dermatotropic DNA viruses that cause lethal disease in humans. Virulence in animal models depends on the virus-encoded bifunctional Z-DNA/double-stranded RNA (dsRNA)-binding protein E3. Here, we report that infection of mouse primary keratinocytes with a vaccinia {Delta}E3L mutant virus triggers the production of beta interferon (IFN-β), interleukin-6 (IL-6), CCL4, and CCL5. None of these immune mediators is produced by keratinocytes infected with wild-type vaccinia virus. The dsRNA-binding domain of E3 suffices to prevent activation of the innate immune response. {Delta}E3L induction of IFN-β, IL-6, CCL4, and CCL5 secretion requires mitochondrial antiviral signaling protein (MAVS; an adaptor for the cytoplasmic viral RNA sensors RIG-I and MDA5) and the transcription factor IRF3. IRF3 phosphorylation is induced in keratinocytes infected with {Delta}E3L, an event that depends on MAVS. The response of keratinocytes to {Delta}E3L is unaffected by genetic ablation of Toll-like receptor 3 (TLR3), TRIF, TLR9, and MyD88.

* Corresponding author. Mailing address for S. Shuman: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 639-7145. Fax: (212) 772-8410. E-mail: s-shuman{at}ski.mskcc.org. Mailing address for L. Deng: Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 610-0785. Fax: (212) 308-0739. E-mail: dengl{at}mskcc.org

{triangledown} Published ahead of print on 20 August 2008.

Journal of Virology, November 2008, p. 10735-10746, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01305-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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