Myxoma virus induces type i interferon production in murine plasmacytoid dendritic cells via a TLR9/myd88-,IRF5/IRF7-, and IFNAR-dependent pathway Journal Article

Authors: Dai, P.; Cao, H.; Merghoub, T.; Avogadri, F.; Wang, W.; Parikh, T.; Fang, C. M.; Pitha, P. M.; Fitzgerald, K. A.; Rahman, M. M.; McFadden, G.; Hu, X.; Houghton, A. N.; Shuman, S.; Deng, L.
Article Title: Myxoma virus induces type i interferon production in murine plasmacytoid dendritic cells via a TLR9/myd88-,IRF5/IRF7-, and IFNAR-dependent pathway
Abstract: Poxviruses are large DNA viruses that replicate in the cytoplasm of infected cells. Myxoma virus is a rabbit poxvirus that belongs to the Leporipoxvirus genus. It causes a lethal disease called myxomatosis in European rabbits but cannot sustain any detectable infection in nonlagomorphs. Vaccinia virus is a prototypal orthopoxvirus that was used as a vaccine to eradicate smallpox. Myxoma virus is nonpathogenic in mice, whereas systemic infection with vaccinia virus can be lethal even in immunocompetent mice. Plasmacytoid dendritic cells (pDCs) are potent type I interferon (IFN)-producing cells that play important roles in antiviral innate immunity. How poxviruses are sensed by pDCs to induce type I IFN production is not well understood. Here we report that infection of primary murine pDCs with myxoma virus, but not with vaccinia virus, induces IFN-α, IFN-β, tumor necrosis factor (TNF), and interleukin-12p70 (IL-12p70) production. Using pDCs derived from genetic knockout mice, we show that the myxoma virus-induced innate immune response requires the endosomal DNA sensor TLR9 and its adaptor MyD88, transcription factors IRF5 and IRF7, and the type I IFN positive-feedback loop mediated by IFNAR1. It is independent of the cytoplasmic RNA sensing pathway mediated by the mitochondrial adaptor molecule MAVS, the TLR3 adaptor TRIF, or the transcription factor IRF3. Using pharmacological inhibitors, we demonstrate that myxoma virus-induced type I IFN and IL-12p70 production in murine pDCs is also dependent on phosphatidylinositol 3-kinase (PI3K) and Akt. Furthermore, our results reveal that the N-terminal Z-DNA/RNA binding domain of vaccinia virulence factor E3, which is missing in the orthologous M029 protein expressed by myxoma virus, plays an inhibitory role in poxvirus sensing and innate cytokine production by murine pDCs. © 2011, American Society for Microbiology.
Keywords: protein kinase b; controlled study; protein expression; unclassified drug; interferon; nonhuman; alpha interferon; animal cell; mouse; animals; mice; mice, knockout; cells, cultured; mus; interleukin 12p70; phosphatidylinositol 3 kinase; mice, inbred c57bl; rna; dendritic cells; dna viruses; proto-oncogene proteins c-akt; murinae; vaccinia virus; protein induction; cytokine production; innate immunity; virus infection; beta interferon; myeloid differentiation factor 88; interferon receptor; receptor, interferon alpha-beta; knockout mouse; tumor necrosis factor; toll like receptor adaptor molecule 1; toll-like receptor 9; poxviridae; variola virus; interferon regulatory factors; phosphatidylinositol 3-kinase; toll like receptor 9; adaptor protein; interferon type i; rna isolation; plasmacytoid dendritic cell; interferon regulatory factor 7; interferon regulatory factor-7; interleukin-12; interferon regulatory factor 3; myxoma virus; interferon regulatory factor 5; mitochondrial antiviral signaling protein; protein ifnar1; orthopoxvirus; oryctolagus cuniculus; leporipoxvirus
Journal Title: Journal of Virology
Volume: 85
Issue: 20
ISSN: 0022-538X
Publisher: American Society for Microbiology  
Date Published: 2011-10-01
Start Page: 10814
End Page: 10825
Language: English
DOI: 10.1128/jvi.00104-11
PROVIDER: scopus
PMCID: PMC3187486
PUBMED: 21835795
Notes: Erratum/Corrigendum issued, see DOI: 10.1128/JVI.06351-11 -- "Export Date: 9 December 2011" - "CODEN: JOVIA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Taha Merghoub
    299 Merghoub
  2. Hua Cao
    11 Cao
  3. Liang Deng
    62 Deng
  4. Stewart H Shuman
    515 Shuman
  5. Weiyi Wang
    18 Wang
  6. Alan N Houghton
    343 Houghton
  7. Tanvi Parikh
    10 Parikh
  8. Peihong Dai
    37 Dai