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

Department of Medicine, Dermatology Service, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Journal of Virology (Impact Factor: 4.44). 09/2008; 82(21):10735-46. DOI: 10.1128/JVI.01305-08
Source: PubMed


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 ΔE3L 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. ΔE3L 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 ΔE3L, an event that depends on MAVS. The response of keratinocytes to ΔE3L is unaffected
by genetic ablation of Toll-like receptor 3 (TLR3), TRIF, TLR9, and MyD88.

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