Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway Journal Article

Authors: Dai, P.; Wang, W.; Cao, H.; Avogadri, F.; Dai, L.; Drexler, I.; Joyce, J. A.; Li, X. D.; Chen, Z.; Merghoub, T.; Shuman, S.; Deng, L.
Article Title: Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway
Abstract: Modified vaccinia virus Ankara (MVA) is an attenuated poxvirus that has been engineered as a vaccine against infectious agents and cancers. Our goal is to understand how MVA modulates innate immunity in dendritic cells (DCs), which can provide insights to vaccine design. In this study, using murine bone marrow-derived dendritic cells, we assessed type I interferon (IFN) gene induction and protein secretion in response to MVA infection. We report that MVA infection elicits the production of type I IFN in murine conventional dendritic cells (cDCs), but not in plasmacytoid dendritic cells (pDCs). Transcription factors IRF3 (IFN regulatory factor 3) and IRF7, and the positive feedback loop mediated by IFNAR1 (IFN alpha/beta receptor 1), are required for the induction. MVA induction of type I IFN is fully dependent on STING (stimulator of IFN genes) and the newly discovered cytosolic DNA sensor cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase). MVA infection of cDCs triggers phosphorylation of TBK1 (Tank-binding kinase 1) and IRF3, which is abolished in the absence of cGAS and STING. Furthermore, intravenous delivery of MVA induces type I IFN in wild-type mice, but not in mice lacking STING or IRF3. Treatment of cDCs with inhibitors of endosomal and lysosomal acidification or the lysosomal enzyme Cathepsin B attenuated MVA-induced type I IFN production, indicating that lysosomal enzymatic processing of virions is important for MVA sensing. Taken together, our results demonstrate a critical role of the cGAS/STING-mediated cytosolic DNA-sensing pathway for type I IFN induction in cDCs by MVA. We present evidence that vaccinia virulence factors E3 and N1 inhibit the activation of IRF3 and the induction of IFNB gene in MVA-infected cDCs. © 2014 Dai et al.
Keywords: controlled study; protein phosphorylation; nonhuman; alpha interferon; animal cell; mouse; animal tissue; gene expression; dendritic cell; enzyme linked immunosorbent assay; western blotting; vaccinia virus; real time polymerase chain reaction; virus infection; gene induction; cathepsin b; virus replication; gene dosage; beta interferon; alpha beta interferon receptor; virus expression; virus dna; adaptor protein; interferon regulatory factor 7; interferon regulatory factor 3; virulence factor; female; article; cyclic amp derivative; cyclic gmp derivative; modified vaccinia virus ankara
Journal Title: PLoS Pathogens
Volume: 10
Issue: 4
ISSN: 1553-7366
Publisher: Public Library of Science  
Date Published: 2014-04-01
Start Page: e1003989
Language: English
DOI: 10.1371/journal.ppat.1003989
PROVIDER: scopus
PMCID: PMC3990710
PUBMED: 24743339
Notes: PLoS Pathog. -- Export Date: 8 July 2014 -- 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. Johanna A Joyce
    67 Joyce
  6. Weiyi Wang
    18 Wang
  7. Peihong Dai
    37 Dai