Salmonella persisters undermine host immune defences during antibiotic treatment
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ABSTRACT:
PROVIDER: PRJNA413814 | ENA |
REPOSITORIES: ENA
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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.
2018-12-07 | GSE104785 | GEO
Project description:Bacterial persister cells are phenotypic variants that exhibit a transient non-growing state and antibiotic tolerance. Here we provide in vitro evidence of Staphylococcus aureus persisters within infected host cells. We show that the bacteria surviving antibiotic treatment within host cells are persisters, displaying biphasic killing and reaching a uniformly non-responsive, non-dividing state when followed at the single-cell level. This phenotype is stable but reversible upon antibiotic removal. Intracellular S. aureus persisters remain metabolically active, but display an altered transcriptomic profile consistent with activation of stress responses, including the stringent response as well as cell-wall stress, SOS and heat-shock responses. These changes are associated with multidrug tolerance after exposure to a single antibiotic. We hypothesize that intracellular S. aureus persisters may constitute a reservoir for relapsing infection, and could contribute to therapeutic failures.
2020-03-25 | GSE139659 | GEO
Project description:Intracellular Staphylococcus aureus persisters upon antibiotic exposure
| PRJNA586837 | ENA
Project description:Staphylococcus aureus can cause severe invasive infections that require prolonged antibiotic treatment. Although S. aureus can easily acquire antibiotic resistance, even fully susceptible bacteria can persist and survive antibiotic therapy, thus complicating treatment. These so-called persisters are phenotypic variants of bacteria characterized by an arrested-growth phenotype that can tolerate high concentrations of chemotherapeutics and are associated with chronic and recurrent infections. Here, we show that S. aureus recovered directly from infection sites, displayed an increased bacterial lag-phase heterogeneity, forming more non-stable small colonies, indicating the presence of dormant bacteria. Infection modelling showed that host-mediated stress, including acidic pH, neutrophil exposure and murine abscesses, as well as antibiotic treatment, promoted formation of persisters both in vitro and in vivo. Proteomics and RNA-sequencing revealed molecular changes in bacteria in response to acidic stress leading to an overall more virulent population. However, after persister-enrichment, S. aureus displayed downregulation of pathways involved in virulence, cell division, and DNA replication, while ribosomal proteins, nucleotide-, and amino acid- metabolic pathways were upregulated, suggesting their requirement to fuel and maintain the persister phenotype. We demonstrate that decreased aconitase activity and ATP-levels as well as accumulation of insoluble proteins correlated with dormancy and growth reactivation cycles. Combination of antibiotics with retinoid derivatives, especially CD1530, significantly reduced both persisters and total bacterial load in a murine infection model. Our study provides an in-depth characterization of S. aureus persisters and shows that treatment failure due to antibiotic persistence could be addressed by using retinoid derivatives in combination with conventional antibiotics.
2021-09-09 | PXD018372 | Pride
Project description:Staphylococcus aureus can cause severe invasive infections that require prolonged antibiotic treatment. Although S. aureus can easily acquire antibiotic resistance, even fully susceptible bacteria can persist and survive antibiotic therapy, thus complicating treatment. These so-called persisters are phenotypic variants of bacteria characterized by an arrested-growth phenotype that can tolerate high concentrations of chemotherapeutics and are associated with chronic and recurrent infections. Here, we show that S. aureus recovered directly from infection sites, displayed an increased bacterial lag-phase heterogeneity, forming more non-stable small colonies, indicating the presence of dormant bacteria. Infection modelling showed that host-mediated stress, including acidic pH, neutrophil exposure and murine abscesses, as well as antibiotic treatment, promoted formation of persisters both in vitro and in vivo. Proteomics and RNA sequencing revealed stress-response reactions in bacteria leading to an overall more virulent population. However, after persister-enrichment, S. aureus displayed down-regulation of pathways involved in virulence, cell division, and DNA replication, while ribosomal proteins, nucleotide-, and amino acid- metabolic pathways were up-regulated, suggesting their requirement to fuel and maintain the persister phenotype. We demonstrate that decreased aconitase activity and ATP-levels as well as accumulation of insoluble proteins correlated with dormancy and growth reactivation cycles. Combination of antibiotics with retinoid derivatives, especially CD1530, significantly reduced both persisters and total bacterial load in a murine infection model. Our study provides an in-depth characterization of S. aureus persisters and shows that treatment failure due to antibiotic persistence could be addressed by using retinoid derivatives in combination with conventional antibiotics.
2021-02-12 | PXD018332 | Pride
Project description:Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against herpes simplex virus 1 (HSV-1) infection. Following the activation of innate immune signalling, HIRA localized at PML-NBs in a Janus-Associated Kinase (JAK), Cyclin Dependent Kinase (CDK), and Sp100-dependent manner. RNA-seq analysis revealed that HIRA promoted the transcriptional upregulation of a broad repertoire of host genes that regulate innate immunity to HSV-1 infection, including those involved in MHC-I antigen presentation, cytokine signalling, and interferon stimulated gene (ISG) expression. ChIP-seq analysis revealed that PML, the principle scaffolding protein of PML-NBs, was required for the enrichment of HIRA onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immunity to virus infection. Our data identifies independent roles for HIRA in the intrinsic silencing of viral gene expression and the induction of innate immune defences to restrict the initiation and propagation of HSV-1 infection, respectively. These intracellular host defences are antagonized by the HSV-1 ubiquitin ligase ICP0, which disrupts the stable recruitment of HIRA to infecting viral genomes and PML-NBs at spatiotemporally distinct phases of infection. Our study highlights the importance of histone chaperones to regulate multiple phases of intracellular immunity to virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.
2019-03-12 | GSE128173 | GEO
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
Project description:Proteomics is the most suitable tool to study persisters with their complex underlying molecular mechanisms from a system-level perspective, but the number of persisters that present naturally is too few for proteomics analysis. Here, we utilized Evo3A, an evolved population with enriched persisters fraction from a recent adaptive laboratory evolution experiment, to study the mechanisms of persistence during ampicillin treatment and resuscitation. Interestingly, the enriched persisters on Evo3A exhibit filamentous morphology upon treatment with ampicillin, and the filaments are getting longer over time. Time-course proteomics study revealed that proteins involved in major carbohydrate metabolism are up-regulated, in particular those involved in the oxidative stress response and act as cellular response to DNA damage. As opposed to the proteome profile during antibiotic treatment, proteins involved in major metabolic processes and ATP generation are down-regulated, while translational proteins and porins are up-regulated in the filaments during resuscitation.
2020-07-13 | PXD016271 | Pride
Project description:Persisters, a dormant and multi-drug tolerant subpopulation that are able to resuscitate after antibiotic treatment, have recently received considerable attentions as the major risk of the relapse of various infectious diseases in clinics. However, due to their low abundance and inherent mutability, it is extremely difficult to study them by proteomics. Here, we developed a magnetic beads-based separation approach to enrich Escherichia coli persisters and then subject them to Filter-Aided Sample Perparation (FASP) followed by LC-MS/MS analysis. We applied spectral counting-based quantitative proteomics to study the proteomic changes of E. coli persisters under high concentration of ampicillin treatment.
2018-10-16 | PXD010590 | Pride
Project description:Staphylococcus aureus causes invasive infections and easily acquires antibiotic resistances. Even antibiotic susceptible S. aureus can survive antibiotic therapy and persist, requiring prolonged treatment and surgical interventions. These so-called persisters display an arrested-growth phenotype, tolerate high antibiotic concentrations and are associated with chronic and recurrent infections. To characterize these persisters, we assessed S. aureus recovered directly from a patient suffering from a persistent infection. We show that host-mediated stress, including acidic-pH, abscesses-environment, and antibiotic exposure promoted persister formation in-vitro and in-vivo. Multi-omics analysis identified molecular changes in S. aureus in response to acid-stress leading to an overall virulent population. However, further analysis of a persister-enriched population revealed major molecular reprogramming in persisters including downregulation of virulence and cell division, and upregulation of ribosomal proteins, nucleotide-, and amino acid- metabolic pathways, suggesting their requirement to fuel and maintain the persister phenotype and highlighting that persisters are not completely metabolically inactive. Additionally, decreased aconitase activity and ATP-levels and accumulation of insoluble proteins involved in transcription, translation and energy-production correlated with persistence in S. aureus, underpinning the molecular mechanisms that drive the persister phenotype. Upon regrowth, these persisters regained their virulence potential and metabolically active phenotype including reduction of insoluble proteins, exhibiting a reversible state, crucial for recurrent infections. We further show that a targeted anti-persister combination therapy using retinoid derivatives and antibiotics significantly reduced lag-phase heterogeneity and persisters in a murine infection model. Our results provide molecular insights into persisters and help explain why persistent S. aureus infections are so difficult-to-treat.
2021-02-12 | PXD022858 | Pride