Vaccinia virus subverts a mitochondrial antiviral signaling protein-dependent innate immune response in keratinocytes through its double-stranded RNA binding protein, E3 Journal Article


Authors: Deng, L.; Dai, P.; Parikh, T.; Cao, H.; Bhoj, V.; Sun, Q.; Chen, Z.; Merghoub, T.; Houghton, A.; Shuman, S.
Article Title: Vaccinia virus subverts a mitochondrial antiviral signaling protein-dependent innate immune response in keratinocytes through its double-stranded RNA binding protein, E3
Abstract: 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. Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Keywords: signal transduction; controlled study; unclassified drug; gene deletion; genetics; nonhuman; animal cell; mouse; animal; animals; mice; animal tissue; cells, cultured; macrophage inflammatory protein 1beta; cell line; cercopithecus aethiops; mice, inbred balb c; keratinocyte; physiology; virology; animalia; rna binding protein; rna-binding proteins; cytokine; immunology; cytokines; bagg albino mouse; cell culture; dna viruses; cercopithecus; vaccinia virus; interleukin 6; binding site; cytokine production; innate immunity; protein structure, tertiary; binding sites; keratinocytes; beta interferon; protein tertiary structure; mitochondrion; myeloid differentiation factor 88; secretion; double stranded rna; virus protein; viral proteins; cricetinae; toll like receptor 9; rabbits; rantes; rabbit; interferon regulatory factor 3; protein e3; e3l protein, vaccinia virus; hamster
Journal Title: Journal of Virology
Volume: 82
Issue: 21
ISSN: 0022-538X
Publisher: American Society for Microbiology  
Date Published: 2008-11-01
Start Page: 10735
End Page: 10746
Language: English
DOI: 10.1128/jvi.01305-08
PUBMED: 18715932
PROVIDER: scopus
PMCID: PMC2573174
DOI/URL:
Notes: --- - "Cited By (since 1996): 11" - "Export Date: 17 November 2011" - "CODEN: JOVIA" - "Source: Scopus"
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Citation Impact
MSK Authors
  1. Taha Merghoub
    306 Merghoub
  2. Hua Cao
    11 Cao
  3. Liang Deng
    64 Deng
  4. Stewart H Shuman
    518 Shuman
  5. Alan N Houghton
    343 Houghton
  6. Tanvi Parikh
    10 Parikh
  7. Peihong Dai
    38 Dai