Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Dissecting the Mycobacterium bovis BCG response to macrophage infection to identify targets for anti-tuberculosis drug and vaccine discovery

ABSTRACT: New strategies are required to reduce the worldwide burden of tuberculosis. Intracellular survival and replication of Mycobacterium tuberculosis after macrophage phagocytosis is a fundamental step in the complex host-pathogen interactions that lead to granuloma formation and disease. Greater understanding of how the bacterium survives and thrives in these environments will inform novel drug and vaccine discovery programmes. Here, we use in-depth RNA sequencing of Mycobacterium bovis BCG from human THP-1 macrophages to describe the mycobacterial adaptations to the intracellular environment. We identify 329 significantly differentially regulated genes, highlighting cholesterol catabolism, methyl-citrate cycle and iron homeostasis as important for mycobacteria inside macrophages. Focused analysis of PE/PPE and cytochrome P450 gene families highlight additional pathways that are upregulated (35 and five respectively) 24h after infection. Comparison of the intracellular transcriptome to gene essentiality and immunogenicity studies identified 15 potential targets that are both required for intracellular survival and induced on infection, and eight genes upregulated that have been demonstrated to be immunogenic in TB patients. Further insight into these new and established targets will support drug and vaccine development efforts.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Mycobacterium tuberculosis variant bovis BCG str. Pasteur 1173P2

SUBMITTER: Simon Waddell

PROVIDER: E-MTAB-11107 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Dissecting the Mycobacterium bovis BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery.

Medley Jamie J Goff Aaron A Bettencourt Paulo J G PJG Dare Madelaine M Cole Liam L Cantillon Daire D Waddell Simon J SJ

Vaccines 20220113 1

New strategies are required to reduce the worldwide burden of tuberculosis. Intracellular survival and replication of Mycobacterium tuberculosis after macrophage phagocytosis is a fundamental step in the complex host-pathogen interactions that lead to granuloma formation and disease. Greater understanding of how the bacterium survives and thrives in these environments will inform novel drug and vaccine discovery programs. Here, we use in-depth RNA sequencing of Mycobacterium bovis ...[more]

PMID: 35062774

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Project description:Pathogenic mycobacteria, such as Mycobacterium tuberculosis, modulate the host immune system to evade clearance and promote long-term persistence, resulting in disease progression or latent infection. Understanding the mechanisms pathogenic mycobacteria use to evade the host immune system is critical to better understanding the pathogenesis of mycobacterial infection. Protein kinase G (PknG) in pathogenic mycobacteria has been shown to play an important role in avoiding clearance by macrophages through blocking phagosome-lysosome fusion; however, the exact mechanism is not completely understood. Here, to investigate the influence of mycobacterial PknG on the phosphoprotein signalling cascades triggered during early events prior to phagocytosis, RAW 264.7 macrophage cell lines were stimulated with M. bovis BCG wild-type and PknG knock-out mutant strains and harvested prior to uptake. After proteolysis, phosphopeptides were enriched via TiO2 columns and subjected to LC-MS/MS to identify differentially phosphorylated peptides between macrophages exposed to the wild-type and PknG knock-out mutant. A total of 1401 phosphosites on 914 unique host proteins were identified. Following phosphoproteome normalisation and differential expression analysis, a total of 149 phosphosites were differentially phosphorylated in the RAW 264.7 macrophages exposed to the wild-type versus the PknG knock-out mutant. A subset of 95 phosphosites was differentially up-regulated in the presence of PknG. In addition, a presence/absence analysis identified 34 phosphosites on 27 host proteins to be exclusively phosphorylated in the presence of PknG. Functional analysis of our data revealed that PknG kinase activity in mycobacteria primes an altered phosphorylation state in host macrophages prior to establishment of infection, through interfering with host spliceosomal and translational machinery, actin cytoskeletal organisation, pro-inflammatory cytokine induction, and programmed cell death, thus establishing a new role for PknG in directing the fate of mycobacteria in macrophage infections.

Dataset Information

Dissecting the Mycobacterium bovis BCG response to macrophage infection to identify targets for anti-tuberculosis drug and vaccine discovery

Publications

Dissecting the <i>Mycobacterium bovis</i> BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Dissecting the Mycobacterium bovis BCG response to macrophage infection to identify targets for anti-tuberculosis drug and vaccine discovery

Publications

Dissecting the &lt;i&gt;Mycobacterium bovis&lt;/i&gt; BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dissecting the <i>Mycobacterium bovis</i> BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery.