Dataset Information

GM-CSF controls Mycobacterium tuberculosis infection by limiting type I IFN-driven neutrophil extracellular trap formation [Lung]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE141205 | GEO | 2020/09/07

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Mycobacteria of the Mycobacterium tuberculosis complex (MTBC) greatly impact on human and animal health worldwide. Mycobacterial life cycle is complex and the mechanisms resulting in pathogen infection and survival in host cells are not fully understood. Eurasian wild boar (Sus scrofa) are natural reservoir hosts for MTBC and a model for mycobacterial infection and tuberculosis (TB). In the wild boar TB model, mycobacterial infection affects the expression of innate and adaptive immune response genes in mandibular lymph nodes and oropharyngeal tonsils and biomarkers have been proposed as correlates with resistance to natural infection. However, the mechanisms used by mycobacteria to manipulate host immune response are not fully characterized. Our hypothesis is that the immune system proteins under-represented in infected animals when compared to uninfected controls are used by mycobacteria to guarantee pathogen infection and transmission. To address this hypothesis, a comparative proteomics approach was used to compare host response between uninfected (TB-) and M. bovis-infected young (TB+) and adult animals with different infection status [TB lesions localized in the head (TB+) or affecting multiple organs (TB++)]. The results identified host immune system proteins that play an important role in host response to mycobacteria. Calcium binding protein A9, Heme peroxidase, Lactotransferrin, Cathelicidin and Peptidoglycan-recognition protein were under-represented in TB+ animals when compared to uninfected TB- controls but protein levels increased as infection progressed in TB++ animals when compared to TB- and/or TB+ adult wild boar. MHCI was the only protein over-represented in TB+ adult wild boar when compared to uninfected TB- controls. The results reported here suggested that M. bovis manipulates host immune response by reducing the production of immune system proteins. However, as infection progresses, wild boar immune response recover to limit pathogen multiplication and promote survival that also facilitates pathogen transmission.

Dataset Information

GM-CSF controls Mycobacterium tuberculosis infection by limiting type I IFN-driven neutrophil extracellular trap formation [Lung]

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets