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Host cholesterol modulates the generation and enrichment of persisters during Mycobacterium tuberculosis infection

ABSTRACT: Host cholesterol modulates the generation and enrichment of persisters during Mycobacterium tuberculosis infection

PROVIDER: PRJNA560771 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9994470_1.fastq.gz	Fastqsanger.gz
	SRR9994470_2.fastq.gz	Fastqsanger.gz
	SRR9994480_1.fastq.gz	Fastqsanger.gz
	SRR9994480_2.fastq.gz	Fastqsanger.gz
	SRR9994490_1.fastq.gz	Fastqsanger.gz

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Host cholesterol modulates the generation and enrichment of persisters during Mycobacterium tuberculosis infection

Project description:A worldwide increase in the frequency of multidrug-resistant and extensively-drug-resistant cases of tuberculosis is mainly due to the therapeutic noncompliance associated with a lengthy treatment regimen. This protracted regimen is attributed to a supposedly nonreplicating and metabolically inert subset of the Mycobacterium tuberculosis (Mtb) population, called ‘persisters’. We have earlier reported that the utilization of host cholesterol is essential for Mtb persistence. However, the mechanism underlying stochastic generation and enrichment of persisters is not fully known. In this study, we showed that cholesterol-induced activation of ribonuclease toxin (VapC12) inhibits translation by targeting proT tRNA and is critical for the generation of persisters in a heterogeneous Mtb population. A vapC12-null mutant strain (ΔvapC12) failed to persist and showed hypervirulence in a guinea pig model of tuberculosis. We identify a novel strategy through which cholesterol-specific activation of a toxin–antitoxin (TA) module in Mtb leads to the persister formation during infection. Our study provides an opportunity for targeting persisters, a new paradigm facilitating tuberculosis drug development.

2020-11-05 | GSE135952 | GEO

Host cholesterol modulates the generation and enrichment of persister population during Mycobacterium tuberculosis infection.

Project description:We previously reported that the utilization of host cholesterol is essential for mycobacterial persistence. In this study, we demonstrated that cholesterol-induced activation of a ribonuclease toxin (VapC12) inhibits translation by targeting proT tRNA in Mtb. The resulting cholesterol-specific growth modulation increases the frequency of the generation of persisters in a heterogeneous Mtb population. A vapC12-null mutant strain (ΔvapC12) failed to persist and demonstrated a hypervirulent phenotype in a guinea pig model of Mtb infection. This is the first study to identify a novel strategy through which cholesterol-specific activation of a toxin–antitoxin (TA) module in Mtb enhances persister formation during infection. In addition to identifying the mechanism, the study provides opportunity for targeting persisters, a new paradigm facilitating tuberculosis drug development.

2020-10-14 | PXD014323 | Pride

A host-directed adjuvant sensitizes intracellular bacterial persisters to antibiotics

Project description:Intracellular bacterial reservoirs contribute to antibiotic treatment failure by fostering metabolically dormant persister cells that are highly tolerant to killing. However, strategies to effectively target intracellular persister cells remain limited. Here, we developed a high-throughput screen to identify compounds that modulate the metabolic activity of intracellular Staphylococcus aureus. The identified compound, KL1, increases intracellular bacterial metabolic activity and sensitizes persister populations of S. aureus to antibiotics, without causing cytotoxicity or bacterial outgrowth. KL1 also exhibits adjuvant activity against intramacrophage Salmonella enterica Typhimurium and Mycobacterium tuberculosis, as well as in murine infection models of S. aureus and S. Typhimurium infection. Transcriptomic analysis and further mechanistic studies reveal that KL1 modulates host immune response genes and suppresses the production of reactive species in host macrophages, alleviating a key inducer of antibiotic tolerance. Our findings highlight the potential to target intracellular persisters by stimulating their metabolism.

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Salmonella persisters undermine host immune defences during antibiotic treatment

Project description:Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters that are considered dormant cells when bacteria are grown in laboratory medium. Non-growing persisters also form following uptake of Salmonella by macrophages but their nature is little understood. Here we show that Salmonella persisters arising during macrophage infection maintain an active state. Persisters reprogram macrophages by means of effectors secreted by the SPI-2 Type 3 Secretion System (T3SS), thereby dampening pro-inflammatory innate immune responses and inducing anti-inflammatory macrophage polarisation. Reprogramming allows non-growing Salmonella to survive for extended periods in their host. Persisters undermining the host immune defences might confer an advantage to the pathogen during relapse once the antibiotic pressure is relieved.

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IL-36/LXR axis modulates cholesterol metabolism and immune defense to Mycobacterium tuberculosis

Project description:Mycobacterium tuberculosis (Mtb) is a life-threatening pathogen in humans. Bacterial infection of macrophages usually triggers strong innate immune mechanisms, including IL-1 cytokine secretion. The newer member of the IL-1 family, IL-36, was recently shown to be involved in cellular defense against Mtb. To unveil the underlying mechanism of IL-36 induced antibacterial activity, we analyzed its role in the regulation of cholesterol metabolism, together with the involvement of Liver X Receptor (LXR) in this process. Here we report that, in Mtb-infected macrophages, IL-36 signaling modulates cholesterol biosynthesis and efflux via LXR. Moreover, IL-36 induces the expression of cholesterol-converting enzymes and the accumulation of LXR ligands, such as oxysterols. Ultimately, both IL-36 and LXR signaling play a role in the regulation of antimicrobial peptides expression and in Mtb growth restriction. These data provide novel evidence for the importance of IL‑36 and cholesterol metabolism mediated by LXR in cellular host defense against Mtb.

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Host cholesterol modulates the generation and enrichment of persister population during Mycobacterium tuberculosis infection.

Project description:Post-translational modifications (PTMs) confer diversity to regulatory mechanisms that control various cellular pathways. Two of the most extensively studied PTMs are phosphorylation and acetylation. Together, they are known to regulate the stability and activity of proteins in both eukaryotes and prokaryotes. Lysine acetylation is known to regulate various cellular pathways conserved across species including mycobacteria. In order to confirm the cholesterol mediated deacetylation of anti-toxin in Mycobacteria, we did mass spectrometry of BCG strain overexpressing the toxin (vapC12)–antitoxin (vapB12)-His(6X) locus grown in glycerol and cholesterol media.

2020-10-16 | PXD022028 | Pride

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Project description:Persisters are a small fraction of growth-arrested phenotypic variants that can survive lethal concentrations of antibiotics but are able to resume growth once antibiotics are stopped. Their formation can be a stochastic process or triggered by environmental cues. In the human pathogen Streptococcus mutans, the canonical peptide-based quorum sensing system is an inducible DNA repair system that is pivotal for bacterial survival. Previous work showed that the CSP signaling peptide is a stress-signaling alarmone that promotes the formation of stress-induced persisters. In this study, we exposed S. mutans to the CSP pheromone to mimic DNA damage conditions and isolated the antibiotic persisters by treating the cultures with ofloxacin. Transcriptome analysis was then performed to evaluate the differential gene expression between the normal stationary phase cells and the persisters. RNA-sequencing revealed that triggered persistence was associated with the up-regulation of genes related to several stress-defense mechanisms, notably, multidrug efflux pumps, the arginine deaminase pathway, and the Opu/Opc system. In addition, we showed that inactivation of the VicK kinase of the YycFG essential two-component regulatory system abolished the formation of triggered persisters via the CSP pheromone. These data contribute to the understanding of the triggered persistence phenotype and may suggest new therapeutic strategies for treating persistent streptococcal infections

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Intracellular Staphylococcus aureus persisters upon antibiotic exposure

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