Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway.
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...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-04-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003989&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841527078966525952 |
|---|---|
| author | Peihong Dai Weiyi Wang Hua Cao Francesca Avogadri Lianpan Dai Ingo Drexler Johanna A Joyce Xiao-Dong Li Zhijian Chen Taha Merghoub Stewart Shuman Liang Deng |
| author_facet | Peihong Dai Weiyi Wang Hua Cao Francesca Avogadri Lianpan Dai Ingo Drexler Johanna A Joyce Xiao-Dong Li Zhijian Chen Taha Merghoub Stewart Shuman Liang Deng |
| author_sort | Peihong Dai |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-17de4a22ac0548bfa09a32d25f4bb012 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2014-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-17de4a22ac0548bfa09a32d25f4bb0122025-01-16T05:30:59ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-04-01104e100398910.1371/journal.ppat.1003989Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway.Peihong DaiWeiyi WangHua CaoFrancesca AvogadriLianpan DaiIngo DrexlerJohanna A JoyceXiao-Dong LiZhijian ChenTaha MerghoubStewart ShumanLiang DengModified 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003989&type=printable |
| spellingShingle | Peihong Dai Weiyi Wang Hua Cao Francesca Avogadri Lianpan Dai Ingo Drexler Johanna A Joyce Xiao-Dong Li Zhijian Chen Taha Merghoub Stewart Shuman Liang Deng Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway. PLoS Pathogens |
| title | Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway. |
| title_full | Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway. |
| title_fullStr | Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway. |
| title_full_unstemmed | Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway. |
| title_short | Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway. |
| title_sort | modified vaccinia virus ankara triggers type i ifn production in murine conventional dendritic cells via a cgas sting mediated cytosolic dna sensing pathway |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003989&type=printable |
| work_keys_str_mv | AT peihongdai modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway AT weiyiwang modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway AT huacao modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway AT francescaavogadri modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway AT lianpandai modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway AT ingodrexler modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway AT johannaajoyce modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway AT xiaodongli modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway AT zhijianchen modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway AT tahamerghoub modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway AT stewartshuman modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway AT liangdeng modifiedvacciniavirusankaratriggerstypeiifnproductioninmurineconventionaldendriticcellsviaacgasstingmediatedcytosolicdnasensingpathway |