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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

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

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

Expression analysis of Mycobacterium avium subsp. paratuberculosis K-10 within macrophage cell line

Project description:Once entering the cell, M. avium subsp.paratuberculosis is known to survive harsh microenvironments, especially those inside activated macrophages. To improve our understanding of M. avium subsp.paratuberculosis pathogenesis, we examined the phagosome maturation associated with transcriptional responses of M. avium subsp.paratuberculosis during macrophage infection. Monitoring cellular markers, only live M. avium subsp.paratuberculosis bacilli were able to prevent phagosome maturation and reduce its acidification. On the transcriptional level, over 300 of M. avium subsp.paratuberculosis genes were significantly, differentially regulated in both naïve and IFN-γ-activated macrophages. These genes include the sigma factor H (sigH) that was shown to be important during persistent infection in M. tuberculosis.

2013-01-22 | GSE43645 | GEO

Global host transcriptional profiles following Mycobacterium avium subsp. paratuberculosis infection in mice

Project description:We focused on how Mycobacterium avium subsp. paratuberculosis influences the subsequent host response to investigate the host immunopathology accompanying the host anti-mycobacterial immune response during Mycobacterium avium subsp. paratuberculosis infection in spleen of mice.

2014-10-31 | GSE62836 | GEO

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