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Dual RNA-sequencing of macrophages infected with Mycobacterium avium reveals host-pathogen interaction in the context of clarithromycin treatment

ABSTRACT: Dual RNA-sequencing of macrophages infected with Mycobacterium avium reveals host-pathogen interaction in the context of clarithromycin treatment

PROVIDER: PRJNA879211 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21525256_1.fastq.gz	Fastqsanger.gz
	SRR21525256_2.fastq.gz	Fastqsanger.gz
	SRR21525257_1.fastq.gz	Fastqsanger.gz
	SRR21525257_2.fastq.gz	Fastqsanger.gz
	SRR21525258_1.fastq.gz	Fastqsanger.gz

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Dual RNA-sequencing of macrophages infected with Mycobacterium avium reveals host-pathogen interaction in the context of clarithromycin treatment

Project description:Background: Mycobacterium avium is an opportunistic pathogen that requires complex multidrug treatment. Macrolides, like clarithromycin, are the cornerstone of treatment, but even macrolide-based treatment regimens have suboptimal outcomes. Combining transcriptomic profiling of macrophages and mycobacteria in an in vitro infection model may increase our understanding of the host-pathogen interaction and the effect of antibiotic treatment. Methods: To investigate the molecular interplay between pathogen and host, we developed an optimized protocol for dual RNA-sequencing of human monocyte-derived macrophages infected with M. avium. Results: Upon phagocytosis, host defense processes including immune activation and pathogen recognition were upregulated, while M. avium upregulated expression of PE/PPE genes, which are important for immune recognition. Clarithromycin did not affect gene regulation of the host; the effect of clarithromycin on M. avium gene expression was very different in RPMI compared to intracellular mycobacteria, likely due to the influence of the host environment on expression of the important regulatory WhiB genes. Conclusions These data identify the distinct stress responses of M. avium upon infection and clarithromycin treatment and underline the importance of taking the intracellular localization and interaction with the host into account when studying antibiotics against intracellular pathogens.

2024-01-01 | GSE213117 | GEO

The potential role of drug transporters and amikacin modifying enzymes in M. avium

Project description:Background: Mycobacterium avium complex (MAC) bacteria cause opportunistic infections in humans. Treatment yields cure rates of 60% and is comprised of a macrolide, a rifamycin and ethambutol; and in severe cases amikacin. Mechanisms of antibiotic tolerance remain mostly unknown. To elucidate these mechanisms, we studied the transcriptomic response to antibiotics and investigated the contribution of efflux and amikacin modification to susceptibility. Methods: M. avium was subjected to subinhibitory concentrations of clarithromycin, amikacin, ethambutol and rifampicin followed by RNA sequencing. Based thereupon, we characterized M. avium efflux pumps and performed time-kill kinetic analysis using each antibiotic in combination with the efflux pump inhibitors (EPIs) berberine, verapamil and CCCP to study the role of efflux on susceptibility. Finally, we studied the modification of amikacin by M. avium using metabolomic analysis. Results: Changes in respiratory state and changes in ribosome binding and protein folding likely contribute to clarithromycin and amikacin tolerance, respectively. No clear drug-specific mechanisms of tolerance are found for ethambutol and rifampicin. Of the EPIs, only berberine increased the susceptibility to rifampicin and clarithromycin. Finally, we show that M. avium, in contrast to M. abscessus, is not able to modify amikacin. Conclusion: M. avium likely relies on a combination of drug-specific and generic mechanisms of antibiotic tolerance including changes in respiratory and metabolic state in addition to drug efflux and target modification. Efflux inhibition can increase susceptibility but this effect is EPI and antibiotic specific. Finally, the lack of amikacin modifying activity in M. avium is important for its activity.

2024-01-01 | GSE213116 | GEO

Whole blood transcriptomics characterize molecular phenotypes of pulmonary Mycobacterium avium complex disease

Project description:Pulmonary Mycobacterium avium complex (MAC) disease shows a range of clinical phenotypes and responses to treatment. While Th1 immunity and neutrophils have been implicated in its pathogenesis, the precise mechanisms remain unclear. Furthermore, comprehensive gene expression analysis in this context are scarce. This study aimed to elucidate the heterogeneity of pulmonary MAC disease by gene expression profiling of whole blood cells. Unsupervised cluster analysis was performed on whole blood gene expression data at 0M. In addition, we also evaluated the variation in gene expression profiles of whole blood cells before (0M) and after starting treatment (1M) with guideline based therapy (GBT; azithromycin [AZM]/clarithromycin [CAM]+ethambutol [EB]+rifampicin [RFP]).

2025-12-08 | GSE288604 | GEO

Exploring transcriptional regulation of Mycobacterium avium subsp. paratuberculosis after human THP-1 cell infection via dual RNA-seq analysis

Project description:Host-pathogen interactions of Mycobacterium avium subsp. paratuberculosis infection at transcriptomic level were investigated in an in vitro macrophage infection model by dual RNA-seq analysis.

2022-09-21 | GSE199476 | GEO

Transcriptional Response of Mycobacterium tuberculosis H37Rv to clarithromycin

Project description:To understand the response of M. tuberculosis (MTB) to the first-line drug clarithromycin, we performed transcriptomics on MTB bacilli exposed to the drug.

2018-09-07 | GSE119571 | GEO

The gene expression profile of Helicobacter pylori exposed to 0.25Î¼g/ml (2ÃMIC) Clarithromycin (CLA) stress

Project description:Analysis of Helicobacter pylori strain 26695 after 20 minutes of 0.25Î¼g/ml Clarithromycin. Results provide insight into the mechanisms employed by the bacterium that help it adapt to Clarithromycin stress In the study presented here, we compared the gene expression profile between H.pylori without CLA treatment and H.pylori treated with 0.25Î¼g/ml Clarithromycin.

2016-07-19 | E-GEOD-84501 | biostudies-arrayexpress

The gene expression profile of Helicobacter pylori exposed to 0.25μg/ml (2×MIC) Clarithromycin (CLA) stress

Project description:Analysis of Helicobacter pylori strain 26695 after 20 minutes of 0.25μg/ml Clarithromycin. Results provide insight into the mechanisms employed by the bacterium that help it adapt to Clarithromycin stress

2016-07-19 | GSE84501 | GEO

Mycobacterium abscessus Extracellular Vesicles Increase Mycobacterial Resistance to Clarithromycin in vitro

Project description:Non-tuberculous Mycobacteria (NTM) are a group of emerging bacterial pathogens that have been identified in cystic fibrosis (CF) patients with microbial lung infections. The treatment of NTM infection in CF patients is challenging due to the natural resistance of NTM species to many antibiotics. Mycobacterium abscessus (M. abscessus) is one of the most common NTM strains found in the airway of CF patients. In our current study, we characterized the extracellular vesicles (EVs) released by drug-sensitive M. abscessus untreated or treated with clarithromycin, one of the well-known anti-NTM drugs. Our data show that clarithromycin treatment increases mycobacterial protein trafficking into EVs as well as the secretion of EVs in M. abscessus culture. Additionally, EVs released by clarithromycin-treated M. abscessus increase M. abscessus resistance to clarithromycin when compared to EVs from untreated M. abscessus. EV proteomic analysis further indicates that EVs released by clarithromycin-treated M. abscessus carry an increased level of 50S ribosomal subunits, the target of clarithromycin. Taken together, our results suggest that mycobacterial EVs play an important role in increasing M. abscessus resistance to clarithromycin treatment.

2025-05-06 | PXD047862 | Pride

An antibiofilm effect against Salmonella typhimurium rdar biofilm formation upon treatment with the macrolide clarithromycin

Project description:Upon biofilm formation, production of extracellular matrix components and alteration in physiology and metabolism allows bacteria to build up multicellular communities which can facilitate nutrient acquisition during unfavorable conditions and provide protection towards various forms of environmental stresses to individual cells. Thus, bacterial cells become tolerant against antimicrobials and the immune system within biofilms. In the current study, we evaluated the antibiofilm activity of the macrolides clarithromycin and azithromycin. Clarithromycin showed antibiofilm activity against rdar (red, dry and rough) biofilm formation of the gastrointestinal pathogen Salmonella typhimurium ATCC14028 Nalr at 1.56 µM subinhibitory concentration in standing culture and dissolved cell aggregates at 15 µM in a microaerophilic environment suggesting that the oxygen level affects the activity of the drug. Treatment with clarithromycin significantly decreased transcription and production of the rdar biofilm activator CsgD, with biofilm genes such as csgB and adrA to be consistently downregulated. While fliA and other flagellar regulon genes were upregulated, apparent motility was downregulated. RNA sequencing showed a holistic cell response upon clarithromycin exposure, whereby not only genes involved in the biofilm-related regulatory pathways, but also genes that likely contribute to intrinsic antimicrobial resistance, and the heat shock stress response were differentially regulated. Most significantly, clarithromycin exposure shifts the cells towards an apparent oxygen- and energy- depleted status, whereby the metabolism that channels into oxidative phosphorylation is downregulated, and energy gain by degradation of propane 1,2-diol, ethanolamine and L-arginine catabolism, potentially also to prevent cytosolic, is upregulated. This analysis will allow the subsequent identification of novel intrinsic antimicrobial resistance determinants.

2020-09-11 | GSE157695 | GEO

Transcriptional profiling of whole blood leukocytes obtained from critically ill patients with sepsis treated with clarithromycin, or not, and healthy particpants

Project description:To evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple-organ dysfunction syndrome. The INntravenous CLArithromycin in Sepsis and multiple organ dysfunction Syndrome trial was a phase 3, randomized, double blind, placebo-controlled clinical study, conducted in 11 intensive care units and 2 Internal Medicine wards in 2 countries. Patients with sepsis, respiratory failure and total sequential organ failure assessment score of ≥7 were enrolled between December 2017 and September 2019. Follow-up lasted 90 days. Patients were randomized to receive 1 gr of intravenous clarithromycin or placebo once daily for 4 consecutive days.

2022-06-30 | GSE196117 | GEO

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