Active nuclear transcriptome analysis reveals inflammasome-dependent mechanism for early neutrophil response to Mycobacterium marinum

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 Mycobacter...

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Bibliographic Details
Published in:Scientific reports Vol. 7; no. 1; pp. 6505 - 14
Main Authors: Kenyon, Amy, Gavriouchkina, Daria, Zorman, Jernej, Napolitani, Giorgio, Cerundolo, Vincenzo, Sauka-Spengler, Tatjana
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 26.07.2017
Nature Publishing Group
Nature Portfolio
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Animals
Biotinylation
Caspase
CRISPR
Disease Models, Animal
Egr-3 protein
Gene expression
Gene Expression Profiling
Genomes
Granuloma
Humanities and Social Sciences
Immunity, Innate
Inflammasomes
Inflammasomes - metabolism
Interleukin 1
Leukocytes (neutrophilic)
Macrophages
multidisciplinary
Mycobacterium Infections, Nontuberculous - pathology
Mycobacterium marinum
Mycobacterium marinum - immunology
Neutrophils
Neutrophils - immunology
Proteolysis
Ribonucleic acid
RNA
Science
Science (multidisciplinary)
Sequence Analysis, RNA
Transcription
Tuberculosis
Zebrafish
ISSN:2045-2322, 2045-2322
Online Access:Get full text
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Summary: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.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-06099-x