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| Status |
Public on Sep 07, 2020 |
| Title |
GM-CSF controls Mycobacterium tuberculosis infection by limiting type I IFN-driven neutrophil extracellular trap formation [Lung] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Tuberculosis (TB) remains the world’s top infectious killer. Understanding how immune mediators determine the outcome of Mycobacterium tuberculosis infection could facilitate the design of better therapies against this devastating disease. GM-CSF mediates protective immunity against TB but the underlying mechanisms remain elusive. To determine the molecular mechanisms underlying the protective role of GM-CSF during M. tuberculosis infection we performed RNA-sequencing analyses of whole blood and lung samples obtained from C57Bl/6 mice infected with HN878 and treated with anti-GM-CSF monoclonal antibody or isotype control. Uninfected mice were also treated and used as uninfected controls. Three weeks post-infection, whole blood and lungs were harvested from each individual mouse and processed for RNA-sequencing. Transcriptomic analyses revealed that during M. tuberculosis infection GM-CSF regulates the expression of genes associated with neutrophil recruitment and activation and type I IFN-inducible genes, which have been previously associated with TB pathogenesis. Further mechanistical studies showed that disease exacerbation driven by GM-CSF blockade during M. tuberculosis infection was type I IFN and neutrophil-dependent and that over-activation of neutrophils by type I IFN induced NET formation at the site of infection. NETs were also found in necrotic lung lesions from patients with pulmonary TB and type I IFN-driven NET formation correlated with increased disease susceptibility in different mouse models of TB. Our findings reveal an important immune network that may play a central role in determining TB outcome.
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| Overall design |
C57Bl/6 female mice were infected with Mycobacterium tuberculosis strain HN878 and treated with anti-GM-CSF monoconal antibody (aGM-CSF) or isotype control (iso) the day prior to infection and then twice a week during the course of the experiment. Uninfected mice were also treated and used as uninfected controls. Three weeks post-infection, whole blood and lungs from each individual mouse were harvested and processed for RNA-sequencing. A total of 39 blood and 39 lung samples were analysed. Experimental groups included: uninfected control mice (5 biological replicates), anti-GM-CSF treated uninfected mice (5 biological replicates), HN878-infected control mice (4 biological replicates), HN878-infected anti-GM-CSF treated mice (5 biological replicates).
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| Contributor(s) |
Moreira-Teixeira L, O'Garra A |
| Citation(s) |
33149141 |
| |
| Submission date |
Nov 29, 2019 |
| Last update date |
Nov 16, 2020 |
| Contact name |
Anne OGarra |
| E-mail(s) |
Anne.OGarra@crick.ac.uk
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| Organization name |
Francis Crick Insititue
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| Lab |
IMMUNOREGULATION AND INFECTION LABORATORY
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| Street address |
1 Midland Road
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| City |
London |
| ZIP/Postal code |
NW1 1AT |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (19)
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| This SubSeries is part of SuperSeries: |
| GSE141207 |
GM-CSF controls Mycobacterium tuberculosis infection by limiting type I IFN-driven neutrophil extracellular trap formation |
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| Relations |
| BioProject |
PRJNA592572 |
| SRA |
SRP234048 |
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