Multisystems analysis of Mycobacterium tuberculosis reveals kinase-dependent remodeling of the pathogen-environment interface
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PXD008968
PROVIDER: PRJNA433880 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Tuberculosis is the leading killer among infectious diseases worldwide. Increasing multi-drug resistance has prompted new approaches for tuberculosis drug development, including targeted inhibition of virulence determinants and of signaling cascades that control many downstream pathways. We used a multisystems approach to determine the effects of a potent small molecule inhibitor of the essential Mycobacterium tuberculosis Ser/Thr protein kinases PknA and PknB. We observed differential phosphorylation of many proteins and extensive changes in gene expression, protein abundance, cell wall lipids and intracellular metabolites. The patterns of these changes indicate regulation by PknA and PknB of several pathways required for cell growth, including ATP synthesis, DNA synthesis and translation. These data also highlight effects on pathways for remodeling of the mycobacterial cell envelope via control of peptidoglycan turnover, lipid content, a SigE-mediated envelope stress response, transmembrane transport systems, and protein secretion systems. Integrated analysis of phosphoproteins, transcripts, proteins, and lipids identified an unexpected pathway whereby threonine phosphorylation of the essential response regulator MtrA decreases its DNA binding activity. Inhibition of this phosphorylation is linked to decreased expression of genes for peptidoglycan turnover, and of genes for mycolyl transferases, with concomitant changes in mycolates and glycolipids in the cell envelope. These findings reveal novel roles for PknA and PknB in regulating multiple essential cell functions and confirm these kinases as potentially valuable targets for new anti-tuberculosis drugs. In addition, these linked multisystems data provide a valuable resource for future targeted investigations into the pathways regulated by these kinases in the M. tuberculosis cell.
2018-03-08 | GSE110508 | GEO
Project description:Tuberculosis is the leading killer among infectious diseases worldwide. The rise of multi-drug resistance has prompted new approaches for tuberculosis drug development, including inhibition of virulence determinants and of signaling cascades that control many downstream pathways. Here we used a multisystems approach to determine the effects of a potent small molecule inhibitor of the essential Mycobacterium tuberculosis Ser/Thr protein kinases PknA and PknB. We observed differential phosphorylation of many proteins and extensive changes in gene expression, protein abundance, cell wall lipids and intracellular metabolites. The patterns of these changes indicate regulation by PknA and PknB of several pathways required for cell growth, including ATP synthesis, DNA synthesis and translation. These data also highlight effects on pathways for remodeling of the mycobacterial cell envelope via control of peptidoglycan turnover, lipid content, a SigE-mediated envelope stress response, transmembrane transport systems, and protein secretion systems. Integrated analysis of phosphoproteins, transcripts, proteins, and lipids identified an unexpected pathway whereby threonine phosphorylation of the essential response regulator MtrA decreases its DNA binding activity. Inhibition of this phosphorylation is linked to decreased expression of genes for peptidoglycan turnover, and of genes for mycolyl transferases, with concomitant changes in mycolates and glycolipids in the cell envelope. These findings reveal novel roles for PknA and PknB in regulating multiple essential cell functions and identify these kinases as potentially valuable targets for new anti-tuberculosis drugs. The linked multisystems data provide a valuable resource for future targeted investigations into the pathways regulated by these kinases in the M. tuberculosis cell.
2018-03-09 | PXD008968 | Pride
Project description: Not available
| S-EPMC5845002 | biostudies-literature
Project description:Cryptococcus spp. are environmental fungi that first must adapt to the host environment before they can cause life-threatening meningitis in immunocompromised patients. Host CO2 concentrations are 100-fold higher than the external environment and strains unable to grow at host CO2 concentrations are not pathogenic. Using a genetic screening and transcriptional profiling approach, we found that the TOR pathway is critical for C. neoformans adaptation to host CO2 partly through Ypk1-dependent remodeling of phosphatidylserine asymmetry at the plasma membrane. We also identified a C. neoformans ABC/PDR transporter (PDR9) that is highly expressed in CO2-sensitive environmental strains, suppresses CO2-induced phosphatidylserine remodeling, and increases susceptibility to host concentrations of CO2. Interestingly, regulation of plasma membrane lipid asymmetry by the TOR-Ypk1 axis is distinct in C. neoformans compared to S. cerevisiae. Finally, host CO2 concentrations suppress the C. neoformans pathways that respond to host temperature (Mpk1) and pH (Rim101), indicating that host adaptation requires a stringent balance among distinct stress responses.
2023-10-24 | GSE241788 | GEO
Project description:Indole signaling at the host-microbiota-pathogen interface
| PRJNA489260 | ENA
Project description:Calcium/calmodulin-dependent protein kinase II (CaMKII) was suggested to mediate ischemic myocardial injury and adverse cardiac remodeling. However, the specific functions of the CaMKII isoforms and splice variants in ischemia/reperfusion (I/R) injury have not been investigated yet. Thus, we studied the roles of the CaMKII isoforms and splice variants in I/R by the use of various CaMKII mutant mice. CaMKIIδC was up-regulated already one day after I/R injury but surprisingly, acute I/R injury was neither affected in CaMKIIδ-deficient mice, CaMKIIδ-deficient mice in which the splice variants CaMKIIδB and C were re-expressed nor in conditional CaMKIIδ/γ double-knockout mice (DKO). In contrast, 5 weeks after I/R, DKO mice were protected against extensive scar formation and cardiac dysfunction. Leukocyte infiltration was not altered one day but five days after I/R, explaining the late effects of CaMKII deletion on post-I/R remodeling. Other than reported before, we demonstrate that CaMKII is not critically involved in the immediate mechanisms that regulate acute I/R injury but in the process of post-infarct remodeling. We analysed 6 groups in total: 3 groups from wild-type control animals and 3 groups from CaMKII delta/gamma double-KO mice. Sham operated animals served as controls in both wild-type and KO animal groups. 2 different time points in ischia/reperfusion operated animals were investigated: 1 day and 5 days post-surgery.
2014-09-08 | E-GEOD-58486 | biostudies-arrayexpress
Project description:Schistosomes infect more than 200 million of the world's poorest people. These parasites live in the vasculature, producing eggs that spur a variety of chronic, potentially life-threatening, pathologies exacerbated by the long lifespan of schistosomes, that can thrive in the host for decades. How schistosomes maintain their longevity in this immunologically hostile environment is unknown. Here, we demonstrate that somatic stem cells in Schistosoma mansoni are biased towards generating a population of cells expressing factors associated exclusively with the schistosome host-parasite interface, a structure called the tegument. We show cells expressing these tegumental factors are short-lived and rapidly turned over. We suggest that stem cell-driven renewal of this tegumental lineage represents an important strategy for parasite survival in the context of the host vasculature.
2015-12-10 | E-GEOD-75861 | biostudies-arrayexpress
Project description:We examined the transcriptional responses of intracellular M. tuberculosis exposed to different front-line drugs during macrophage infection. Our data reveal that Mtb experiences amplification of multiple host-derived pressures following drug exposure. The stresses from the host environment have a dominant impact on Mtb gene expression to the extent that the transcriptional profiles cluster according to environment, ie. broth vs host cell, rather than drug.
2016-02-21 | GSE62942 | GEO
Project description:Shewanella sp. strain:Environment | isolate:Environment Genome sequencing
| PRJNA485866 | ENA