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Experimental selection of long-term intracellular mycobacteria

ABSTRACT: Some intracellular bacteria are known to cause long-term infections for periods of time that last decades without compromising the viability of the host. Although of critical importance, the changes that intracellular bacteria suffer during this long process of residence in a host cell environment remain obscure. Here, we report an experimental approach to study the adaptations of intracellular mycobacteria forced by a long-term intracellular lifestyle. Long-term infection of host macrophages with mycobacteria was maintained for a period of years. Mycobacteria in the long-term infected macrophages underwent an adaptation process leading to impaired phenolic glycolipids (PGL) synthesis, preference for glucose as a carbon source and neutral lipids accumulation. These changes correlated with increased survival of mycobacteria in macrophages and mice during re-infection and specific expression of stress- and survival-related genes. Our findings identify bacterial traits implicated in the establishment of long-term cellular infections and represent a tool for understanding the physiological states of bacteria living in fluctuating intracellular environments.

ORGANISM(S): Mycobacterium tuberculosis variant bovis BCG

PROVIDER: GSE49976 | GEO | 2014/12/31

SECONDARY ACCESSION(S): PRJNA215740

REPOSITORIES: GEO

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Mycobacterium tuberculosis variant bovis BCG

Project description:Experimental selection of long-term intracellular mycobacteria

| PRJNA215740 | ENA

Single-cell RNA-seq reveals disparate macrophage responses to intracellular Salmonella

Project description:Intracellular bacterial pathogens can exhibit large heterogeneity in growth rate inside host cells with major consequences for the infection outcome. If and how the host responds to this heterogeneity remains poorly understood. Here, we combined a fluorescent reporter of bacterial cell division with single-cell RNA-seq analysis to study the macrophage response to different intracellular states of the model pathogen Salmonella enterica serovar Typhimurium. The transcriptomes of individual infected macrophages revealed a spectrum of functional host response states to dividing and non-dividing bacteria. Intriguingly, macrophages harboring non-dividing Salmonella display hallmarks of the pro-inflammatory M1 polarization state and differ little from bystander cells, suggesting that non-dividing bacteria evade recognition by intracellular immune receptors. By contrast, macrophages containing dividing bacteria have turned into an anti-inflammatory, M2-like state, as if fast-growing intracellular Salmonella overcome host defense by reprogramming macrophage polarization. Additionally, our clustering approach reveals intermediate host functional states between these extremes. Altogether our data suggest that gene expression variability in infected host cells shapes different cellular environments, some of which may favor a growth arrest of Salmonella facilitating immune evasion and the establishment of a long-term niche; while others allow Salmonella to escape intracellular antimicrobial activity and proliferate.

2016-09-14 | GSE79363 | GEO

Arginine utilization following mycobacteria infection in macrophages is dependent on autocrine-paracrine signaling

Project description:Nitric oxide (NO) produced by macrophages (MØs) is toxic to both host tissues and invading pathogens and its regulation is therefore essential to suppress host cytotoxicity. MØ arginase 1 (Arg1) inhibits NO production by competing with NO synthases for arginine, the common substrate of NO synthases and arginases. Two signal transduction pathways control Arg1 expression in MØs. First, a MyD88-dependent pathway induces Arg1 in intracellular infections, while a second Stat6-dependent pathway is required for Arg1 expression in alternativelyactivated MØs. We found that mycobacteria-infected MØs produce soluble factors that induce Arg1 in an autocrine-paracrine manner via Stat3. We identify these factors as IL-6, IL-10 and GCSF. We further establish that Arg1 expression is controlled by the MyD88-dependent production of IL-6, IL-10 and G-CSF rather than cell intrinsic MyD88 signaling to Arg1. Our data reveal the MyD88-dependent pathway of Arg1induction following BCG infection requires Stat3 activation and may result in the development of an immunosuppressive niche in granulomas due to the induced Arg1 production in surrounding uninfected MØs We used microarrays to perform genome wide expression analysis in mycobacteria-infected macrophages from C57Bl/6 WT and MyD88-knockout mice.

2010-07-14 | E-GEOD-22935 | biostudies-arrayexpress

Cyclipostins and Cyclophostin analogs impair growth of Mycobacterium abscessus by inhibiting enzymes involved in many physiological processes

Project description:Mycobacterium abscessus is nowadays under the spotlight of the scientific community. This pathogenic mycobacteria is indeed responsible for a wide spectrum of infections involving mostly pulmonary infections in patients with cystic fibrosis. M. abscessus is intrinsically resistant to a broad range of antibiotics, including most antitubercular drugs, and is considered the most pathogenic and chemotherapy-resistant rapidly growing mycobacterium. Consequently, with very limited treatment options, the development of new therapeutic approaches to fight this pathogen are urgently needed. 38 new analogs of Cyclipostins & Cyclophostin (CyC), compounds naturally produced by Streptomyces species, have been synthesized. Their antibacterial activities against clinical isolates belonging to the M. chelonae-abscessus clade, as well as Gram-negative and Gram-positive bacteria have been evaluated by the REMA method. The intracellular activities of the CyC against intramacrophagic M. abscessus have also been investigated and compared to those of imipenem. The CyCs displayed very low toxicity towards host cells and their inhibitory activity was exclusively restricted to mycobacteria. The best candidate, CyC17, showed a high selectivity for mycobacteria with MIC values (<2 up to 40 µg/mL) comparable to those of most classical antibiotics used to treat M. abscessus infections. Of importance, several CyCs were active against extracellular M. abscessus growth (i.e., CyC17 / CyC18β / CyC25 / CyC26) or against intracellular mycobacteria inside macrophages (i.e., CyC7α,β / CyC8α,β) with MIC values similar to or better than those of standard antibiotics. Based on these results, we intended to identify the potential target enzymes of CyC17/CyC26 in M. abscessus by activity-based protein profiling (ABPP) approach coupled with mass spectrometry differential analysis.

2019-10-08 | PXD014255 | Pride

Intracellular transcriptional adaptation of Mycobacterium tuberculosis complex (MTC) clinical isolates inside activated murine macrophages

Project description:This study uses microarray analyses to examine transcriptional responses of Mycobacterium tuberculosis complex clinical isolates to phagosomal cues encountered inside activated (IFN-gamma+LPS) murine bone marrow-derived macrophages 24hr post-infection. Transcript levels of intracellular mycobacteria were compared to extracellular bacteria of the same strain (An aliquot of the inoculum used to infect macrophages was incubated in the absence of macrophages for 24hr in an identical flask). Set of arrays that are part of repeated experiments Keywords: Biological Replicate Biological Replicate Computed

2010-07-09 | E-GEOD-21113 | biostudies-arrayexpress

Intracellular transcriptional adaptation of Mycobacterium tuberculosis complex (MTC) clinical isolates inside resting murine macrophages

Project description:This study uses microarray analyses to examine transcriptional responses of Mycobacterium tuberculosis complex clinical isolates to phagosomal cues encountered inside resting murine bone marrow-derived macrophages 24hr post-infection. Transcript levels of intracellular mycobacteria were compared to extracellular bacteria of the same strain (An aliquot of the inoculum used to infect macrophages was incubated in the absence of macrophages for 24hr in an identical flask). Set of arrays that are part of repeated experiments Keywords: Biological Replicate Biological Replicate Computed

2010-07-09 | E-GEOD-21112 | biostudies-arrayexpress

Global gene networks of canine monocyte-derived macrophages infected with Mycobacterium intracellulare

Project description:An opportunistic intracellular pathogen Mycobacterium intracellulare, a member of the nontuberculous mycobacteria (NTM) cluster, causes respiratory disease in immunosuppressed hosts, including companion dogs. The purpose of this study is to investigate a host-M.intracellulare interactome in canine monocyte-derived macrophages during the infection.

2020-09-24 | GSE158425 | GEO

Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages.

Project description:Mycobacterium tuberculosis thrives within macrophages by residing in phagosomes and preventing them from maturing and fusing with lysosomes. A parallel transcriptional survey of intracellular mycobacteria and their host macrophages revealed signatures of heavy metal poisoning. In particular, mycobacterial genes encoding heavy metal efflux P-type ATPases CtpC, CtpG, and CtpV, and host cell metallothioneins and zinc exporter ZnT1, were induced during infection. Consistent with this pattern of gene modulation, we observed a burst of free zinc inside macrophages, and intraphagosomal zinc accumulation within a few hours postinfection. Zinc exposure led to rapid CtpC induction, and ctpC deficiency caused zinc retention within the mycobacterial cytoplasm, leading to impaired intracellular growth of the bacilli. Thus, the use of P(1)-type ATPases represents a M. tuberculosis strategy to neutralize the toxic effects of zinc in macrophages. We propose that heavy metal toxicity and its counteraction might represent yet another chapter in the host-microbe arms race. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-122]

2012-01-27 | E-BUGS-122 | biostudies-arrayexpress

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

Intracellular transcriptional adaptation of Mycobacterium tuberculosis complex (MTC) clinical isolates inside resting murine macrophages

Project description:This study uses microarray analyses to examine transcriptional responses of Mycobacterium tuberculosis complex clinical isolates to phagosomal cues encountered inside resting murine bone marrow-derived macrophages 24hr post-infection. Transcript levels of intracellular mycobacteria were compared to extracellular bacteria of the same strain (An aliquot of the inoculum used to infect macrophages was incubated in the absence of macrophages for 24hr in an identical flask). Set of arrays that are part of repeated experiments Keywords: Biological Replicate

2010-07-09 | GSE21112 | GEO

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