Active nuclear transcriptome analysis reveals inflammasome-dependent mechanism for early neutrophil response to Mycobacterium marinum
Abstract The mechanisms governing neutrophil response to Mycobacterium tuberculosis remain poorly understood. In this study we utilise biotagging, a novel genome-wide profiling approach based on cell type-specific in vivo biotinylation in zebrafish to analyse the initial response of neutrophils to M...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-06099-x |
| _version_ | 1818842098636423168 |
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| author | Amy Kenyon Daria Gavriouchkina Jernej Zorman Giorgio Napolitani Vincenzo Cerundolo Tatjana Sauka-Spengler |
| author_facet | Amy Kenyon Daria Gavriouchkina Jernej Zorman Giorgio Napolitani Vincenzo Cerundolo Tatjana Sauka-Spengler |
| author_sort | Amy Kenyon |
| collection | DOAJ |
| description | Abstract The mechanisms governing neutrophil response to Mycobacterium tuberculosis remain poorly understood. In this study we utilise biotagging, a novel genome-wide profiling approach based on cell type-specific in vivo biotinylation in zebrafish to analyse the initial response of neutrophils to Mycobacterium marinum, a close genetic relative of M. tuberculosis used to model tuberculosis. Differential expression analysis following nuclear RNA-seq of neutrophil active transcriptomes reveals a significant upregulation in both damage-sensing and effector components of the inflammasome, including caspase b, NLRC3 ortholog (wu: fb15h11) and il1β. Crispr/Cas9-mediated knockout of caspase b, which acts by proteolytic processing of il1β, results in increased bacterial burden and less infiltration of macrophages to sites of mycobacterial infection, thus impairing granuloma development. We also show that a number of immediate early response genes (IEGs) are responsible for orchestrating the initial neutrophil response to mycobacterial infection. Further perturbation of the IEGs exposes egr3 as a key transcriptional regulator controlling il1β transcription. |
| first_indexed | 2024-12-19T04:36:35Z |
| format | Article |
| id | doaj.art-05540afead234068a7e0b6a9d5e50ad4 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T04:36:35Z |
| publishDate | 2017-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-05540afead234068a7e0b6a9d5e50ad42022-12-21T20:35:44ZengNature PortfolioScientific Reports2045-23222017-07-017111410.1038/s41598-017-06099-xActive nuclear transcriptome analysis reveals inflammasome-dependent mechanism for early neutrophil response to Mycobacterium marinumAmy Kenyon0Daria Gavriouchkina1Jernej Zorman2Giorgio Napolitani3Vincenzo Cerundolo4Tatjana Sauka-Spengler5University of Oxford, Weatherall Institute of Molecular Medicine, Radcliffe Department of MedicineUniversity of Oxford, Weatherall Institute of Molecular Medicine, Radcliffe Department of MedicineUniversity of Oxford, Weatherall Institute of Molecular Medicine, Radcliffe Department of MedicineUniversity of Oxford, Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, Radcliffe Department of MedicineUniversity of Oxford, Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, Radcliffe Department of MedicineUniversity of Oxford, Weatherall Institute of Molecular Medicine, Radcliffe Department of MedicineAbstract The mechanisms governing neutrophil response to Mycobacterium tuberculosis remain poorly understood. In this study we utilise biotagging, a novel genome-wide profiling approach based on cell type-specific in vivo biotinylation in zebrafish to analyse the initial response of neutrophils to Mycobacterium marinum, a close genetic relative of M. tuberculosis used to model tuberculosis. Differential expression analysis following nuclear RNA-seq of neutrophil active transcriptomes reveals a significant upregulation in both damage-sensing and effector components of the inflammasome, including caspase b, NLRC3 ortholog (wu: fb15h11) and il1β. Crispr/Cas9-mediated knockout of caspase b, which acts by proteolytic processing of il1β, results in increased bacterial burden and less infiltration of macrophages to sites of mycobacterial infection, thus impairing granuloma development. We also show that a number of immediate early response genes (IEGs) are responsible for orchestrating the initial neutrophil response to mycobacterial infection. Further perturbation of the IEGs exposes egr3 as a key transcriptional regulator controlling il1β transcription.https://doi.org/10.1038/s41598-017-06099-x |
| spellingShingle | Amy Kenyon Daria Gavriouchkina Jernej Zorman Giorgio Napolitani Vincenzo Cerundolo Tatjana Sauka-Spengler Active nuclear transcriptome analysis reveals inflammasome-dependent mechanism for early neutrophil response to Mycobacterium marinum Scientific Reports |
| title | Active nuclear transcriptome analysis reveals inflammasome-dependent mechanism for early neutrophil response to Mycobacterium marinum |
| title_full | Active nuclear transcriptome analysis reveals inflammasome-dependent mechanism for early neutrophil response to Mycobacterium marinum |
| title_fullStr | Active nuclear transcriptome analysis reveals inflammasome-dependent mechanism for early neutrophil response to Mycobacterium marinum |
| title_full_unstemmed | Active nuclear transcriptome analysis reveals inflammasome-dependent mechanism for early neutrophil response to Mycobacterium marinum |
| title_short | Active nuclear transcriptome analysis reveals inflammasome-dependent mechanism for early neutrophil response to Mycobacterium marinum |
| title_sort | active nuclear transcriptome analysis reveals inflammasome dependent mechanism for early neutrophil response to mycobacterium marinum |
| url | https://doi.org/10.1038/s41598-017-06099-x |
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