Elucidating the effects of the macrophage environment on the efficacy of anti-mycobacterial drugs
Ontology highlight
ABSTRACT:
ORGANISM(S): Mycobacterium tuberculosis Mycobacterium tuberculosis CDC1551
PROVIDER: GSE62942 | GEO | 2016/02/21
SECONDARY ACCESSION(S): PRJNA266241
REPOSITORIES: GEO
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Project description:Heterogeneity of host cells as well as bacteria residing within them has been known to induce drug tolerance in pathogens. In Mycobacterium tuberculosis, particularly, drug tolerance within host is a major hurdle in the path to attain a sterlising cure. Reports have shown how residence of Mtb within macrophages makes the pathogen refractory to anti-TB therapy. However, the mechanisms responsible for induction of tolerance to antibiotics, particularly in resting macrophages where Mtb continues to actively replicate, is yet to be deciphered. Reports have suggested that heterogeneity induced in Mtb by cues sensed in the host environment could be a contributing factor to drug tolerance. With regard to this, differences in redox physiology of intra-macrophage Mtb (mid-point potential of the major cytosolic redox buffer in Mtb, mycothiol- EMSH) have been shown to play a role in influencing antibiotic-mediated killing. In this study, we have attempted to analyse the trascriptomic profiles of individual redox sub-populations of Mtb from within macrophages- viz., the EMSH-reduced bacteria with mid-point potential ranging between -285 and -310 mV, shown to be most refractory to killing by front-line anti-TB antibiotics inside macrophages, as well as EMSH-basal bacteria with mid-point potential ranging between -270 and -280 mV, with a much higher degree of antibiotic susceptibility within macrophages. Analysing gene expression level differences between these bacterial sub-populations would help in providing a mechanistic understanding of drug tolerance in Mtb, bred from phenotypic heterogeneity in the pathogen.
2019-09-13 | GSE123267 | GEO
Project description:Mycobacterium tuberculosis (Mtb) infection can widely affect host signal transduction and protein function. Recent studies have revealed that Mtb virulence factors could regulate host immune activation and promote intracellular survival of the pathogen. However, no systematic research has been conducted on Mtb infection. Here, we analyzed mycobacteria-infected cells using multi-omics (proteomics, phosphoproteomics, transcriptomics, and interactomics) and observed that mycobacteria could regulate host alternative splicing by decreasing spliceosomes phosphorylation level. Using phosphoproteomics and interactomics, we connected decreased host phosphorylation with mycobacterial serine/threonine protein phosphatase PstP and observed that Pstp can regulate host Pla2g7 gene alternative splicing by dephosphorylating the spliceosome RBMX S189 site. Further studies showed that PLA2G7 exon9 including rather than excluding form, promotes the inflammatory response. In conclusion, our findings revealed the global landscape and Pstp functions during Mtb infection, which could lead to a deeper understanding of Mtb-host interactions.
2024-12-01 | GSE264715 | GEO
Project description:The identification of multidrug resistant (MDR), extensively and totally drug resistant Mycobacterium tuberculosis (Mtb), in vulnerable sites such as Mumbai, is a grave threat to the control of tuberculosis. The current study aimed at explaining the rapid expression of MDR in Directly Observed Treatment Short Course (DOTS) compliant patients, represents the first study comparing global transcriptional profiles of 3 pairs of clinical Mtb isolates, collected longitudinally at initiation and completion of DOTS. While the isolates were drug susceptible (DS) at onset and MDR at completion of DOTS, they exhibited identical DNA fingerprints at both points of collection. The whole genome transcriptional analysis was performed using total RNA from H37Rv and 3 locally predominant spoligotypes viz. MANU1, CAS and Beijing, hybridized on MTBv3 (BuG@S) microarray, and yielded 36, 98 and 45 differentially expressed genes respectively. Genes encoding transcription factors (sig, rpoB), cell wall biosynthesis (emb genes), protein synthesis (rpl) and additional central metabolic pathways (ppdK, pknH, pfkB) were found to be down regulated in the MDR isolates as compared to the DS isolate of the same genotype. Up regulation of drug efflux pumps, ABC transporters, trans-membrane proteins and stress response transcriptional factors (whiB) in the MDR isolates was observed. The data indicated that Mtb, without specific mutations in drug target genes may persist in the host due to additional mechanisms like drug efflux pumps and lowered rate of metabolism. Furthermore this population of Mtb, which also showed reduced DNA repair activity, would result in selection and stabilization of spontaneous mutations in drug target genes, causing selection of a MDR strain in the presence of drug pressures. Efflux pump such as drrA may play a significant role in increasing fitness of low level drug resistant cells and assist in survival of Mtb till acquisition of drug resistant mutations with least fitness cost. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-134]
2013-04-24 | E-BUGS-134 | biostudies-arrayexpress
Project description:Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, a chronic granulomatous disease. Mtb is mostly restricted to humans and seldom causes disease in animals. M. bovis (Mbv) on the other hand causes tuberculosis in cows (bovine tuberculosis) and several wild animals. Each of these pathogens therefore has unique host adaptations and the host- and pathogen-specific factors driving this differential tropism still remain largely unknown. Here we profiled the secretomes of Mtb- and Mbv-infected bovine macrophages to characterise host-specific responses to each pathogen.
2021-03-11 | PXD017949 | Pride
Project description:Ferroptosis is an iron-dependent programmed cell death caused by lipid peroxidation. Emerging evidence suggests several pathogens manipulate ferroptosis as a way for pathogen propagation, but the underlying mechanisms remain largely elusive. Here, we report that PtpA, secreted by intracellular pathogen Mycobacterium tuberculosis (Mtb), is a ferroptosis inducer during infection. Mechanistically, Mtb PtpA entries into the nucleus through the RaDAR pathway depending on the conserved cysteine 11 site, but not canonical ARs motif. Then, PtpA functions as an adaptor to increase the affinity between protein arginine methyltransferase 6 (PRMT6) with its substrate histone H3, thus promoting the asymmetric dimethylation of histone H3 at arginine 2 (H3R2me2a), leading to repression of GPX4 gene expression and the ensuing ferroptosis. Accordingly, disrupting nucleus entry site or PRMT6-interacting motif of PtpA markedly eliminates the PtpA-induced ferroptosis in host cells. These findings find a new motif involved in intracellular pathogens effectors for entering host nucleus, and reveal an unrecognized regulatory role of PtpA as an activator of methyltransferases PRMT6 to promote ferroptosis in host nuclear, providing fresh insights into the mechanism of Mtb-induced cell death.
2023-02-04 | GSE199069 | GEO
Project description:Mycobacterial arabinogalactan (AG) is an essential cell wall component of Mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Yet, it is unclear whether mycobacterial AG is a pathogen-associated molecular pattern (PAMP) with an elusive pattern recognition receptor (PRR). Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibited cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increased survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacted with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associated with transforming growth factor β-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocked AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravated the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.
2021-02-17 | GSE166850 | GEO
Project description:This experiment is to compare the transcription patterns of mouse macrophages (J774A.1) infected with BCG, H37Ra and M. smegmatis under high multiplicity of infection (MOI). Through the global transcriptome profiling study, we define a pathogen specific host gene expression pattern and indicate that SRC likely plays a central role in regulating multiple unique signaling pathways activated by MTB infection. Mycobacterium tuberculosis (MTB) infects an estimated one-third of the global population and is one of the main causes of mortality due to an infectious agent.
2014-03-31 | GSE45675 | GEO
Project description:Mycobacterium tuberculosis (Mtb) depends on protein secretion systems for intracellular survival and virulence. The major virulence determinant and ESX-1 dependent effector protein EsxA causes tissue damage and necrosis which promotes spread and dissemination of the bacterium. We developed a fibroblast survival assay (FSA) that exploits this phenotype by selecting for molecules that protect host cells from Mtb-induced lysis. Hit compounds identified in this high-throughput screen blocked the secretion of EsxA thus promoting phagosome maturation which led to substantially reduced bacterial burden in activated macrophages. Target identification studies performed on these drugs led to discovery of a benzothiophene containing histidine kinase inhibitor and a benzyloxybenzylidine hydrazine compound affecting mycobacterial metal ion homeostasis which enabled us to reveal zinc stress as a signal for EsxA secretion. Collectively, this novel drug screening approach can help to tackle the mounting problem of antibiotic-resistant mycobacteria by largely extending the target spectrum of small molecule libraries.
2015-05-15 | GSE58314 | GEO
Project description:Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), latently infects one quarter of the world’s population. The rise of multidrug resistant (MDR) Mtb infections worldwide presents a significant obstacle to curb TB globally. While human studies report dysregulated immune responses in MDR TB patients, there is a lack of clear understanding of the host-pathogen interactions following MDR Mtb infection. We recently showed that Mtb carrying a rifampicin drug resistance (RDR)-conferring single nucleotide polymorphism in the RNA polymerase-B gene (Mtb rpoB-H445Y) can modulate host macrophage metabolic reprogramming by production of Type I IFNs. Here, using a mouse model, we have characterized the host immune response in vivo following RDR Mtb infection. We show that despite establishment of Mtb infection in the lung and dissemination to the peripheral organs, lung myeloid and lymphoid immune responses to RDR Mtb is suppressed through a Type I IFN-dependent mechanism. These results coincide with a muted responses in the bone marrow hematopoietic stem and progenitor cells (HSPCs) and progenitors following RDR Mtb infection. These results suggest that host directed therapeutics and vaccines for drug resistant TB may need to be target specific host immune pathways for protection.
2022-06-01 | GSE176423 | GEO
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2024-04-03 | GSE249401 | GEO