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Enhancers of host immune tolerance to bacterial infection discovered using linked computational and experimental approaches II

ABSTRACT: Current therapeutic strategies against bacterial infections focus on reduction of pathogen load using antibiotics; however, stimulation of host tolerance to infection in the presence of pathogens might offer an alternative approach. We used computational transcriptomics and Xenopus laevis embryos to discover infection response pathways, identify potential tolerance inducer drugs, and validate their ability to induce broad tolerance. Xenopus exhibits natural tolerance to Acinetobacter baumanii, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae bacteria, whereas Aeromonas hydrophila and Pseudomonas aeruginosa produce lethal infections. Transcriptional profiling led to definition of a 20-gene signature that discriminates between tolerant and susceptible states, as well as identification of a more active tolerance response to gram negative compared to gram positive bacteria. Gene pathways associated with active tolerance in Xenopus, including some involved in metal ion binding and hypoxia, were found to be conserved across species, including mammals, and administration of a metal chelator (deferoxamine) or a HIF-1 agonist (1,4-DPCA) in embryos infected with lethal A. hydrophila increased survival despite high pathogen load. These data demonstrate the value of combining the Xenopus embryo infection model with computational multi-omics analyses for mechanistic discovery and drug repurposing to induce host tolerance to bacterial infections.

ORGANISM(S): Xenopus laevis

PROVIDER: GSE196424 | GEO | 2022/06/16

REPOSITORIES: GEO

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Enhancers of host immune tolerance to bacterial infection discovered using linked computational and experimental approaches I

Project description:Current therapeutic strategies against bacterial infections focus on reduction of pathogen load using antibiotics; however, stimulation of host tolerance to infection in the presence of pathogens might offer an alternative approach. We used computational transcriptomics and Xenopus laevis embryos to discover infection response pathways, identify potential tolerance inducer drugs, and validate their ability to induce broad tolerance. Xenopus exhibits natural tolerance to Acinetobacter baumanii, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae bacteria, whereas Aeromonas hydrophila and Pseudomonas aeruginosa produce lethal infections. Transcriptional profiling led to definition of a 20-gene signature that discriminates between tolerant and susceptible states, as well as identification of a more active tolerance response to gram negative compared to gram positive bacteria. Gene pathways associated with active tolerance in Xenopus, including some involved in metal ion binding and hypoxia, were found to be conserved across species, including mammals, and administration of a metal chelator (deferoxamine) or a HIF-1 agonist (1,4-DPCA) in embryos infected with lethal A. hydrophila increased survival despite high pathogen load. These data demonstrate the value of combining the Xenopus embryo infection model with computational multi-omics analyses for mechanistic discovery and drug repurposing to induce host tolerance to bacterial infections.

2022-06-16 | GSE196422 | GEO

Gene expression patterns in blood leukocytes discriminate patients with acute infections

Project description:Each infectious agent represents a unique combination of pathogen-associated molecular patterns that interact with specific pattern-recognition receptors expressed on immune cells. Therefore, we surmised that the blood immune cells of individuals with different infections might bear discriminative transcriptional signatures. Gene expression profiles were obtained for 131 peripheral blood samples from pediatric patients with acute infections caused by influenza A virus, Gram-negative (Escherichia coli) or Gram-positive (Staphylococcus aureus and Streptococcus pneumoniae) bacteria. Thirty-five genes were identified that best discriminate patients with influenza A virus infection from patients with either E coli or S pneumoniae infection. These genes classified with 95% accuracy (35 of 37 samples) an independent set of patients with either influenza A, E coli, or S pneumoniae infection. A different signature discriminated patients with E coli versus S aureus infections with 85% accuracy (34 of 40). Furthermore, distinctive gene expression patterns were observed in patients presenting with respiratory infections of different etiologies. Thus, microarray analyses of patient peripheral blood leukocytes might assist in the differential diagnosis of infectious diseases. Keywords: expression analysis

2007-03-16 | GSE6269 | GEO

Transcription profiling of human blood leukocytes to discriminate patients with acute infections

2009-03-13 | E-GEOD-6269 | biostudies-arrayexpress

Impaired PPARɣ activation by cadmium exacerbates infection-induced lung injury

Project description:Emerging data indicates an association between environmental heavy metal exposure and lung disease, including lower respiratory tract infections (LRTIs). Here, we show by single cell RNA-sequencing an increase in Pparg gene expression in lung macrophages from mice exposed to cadmium and/or infected with S. pneumoniae. However, the heavy metal cadmium or infection mediated an inhibitory post-translational modification of peroxisome proliferator-activated receptor ɣ (PPARɣ) to exacerbate LRTIs. Cadmium and infection increased ERK activation to regulate PPARɣ degradation in monocyte-derived macrophages. Mice harboring a conditional deletion of Pparg in monocyte-derived macrophages had more severe S. pneumoniae infection after cadmium exposure, showed greater lung injury, and had increased mortality. Inhibition of ERK activation with BVD-523 protected mice from lung injury after cadmium exposure or infection. Moreover, subjects residing in areas of high air cadmium levels had increased cadmium concentration in their BAL fluid and showed PPARɣ inhibition that was mediated, at least in part, by ERK activation in isolated BAL cells. These observations suggest that impaired activation of PPARɣ in monocyte-derived macrophages exacerbates lung injury and the severity of LRTIs.

2023-09-07 | GSE225386 | GEO

Engineered live bacteria suppress Pseudomonas aeruginosa lung infection in mouse and dissolve biofilm in endotracheal tubes from patients

Project description:Engineered live bacteria could provide a new modality for treating lung infections , a major cause of mortality worldwide. Here, we engineered a genome-reduced human lung bacterium, Mycoplasma pneumoniae, to treat ventilator-associated pneumonia (VAP), a disease with high hospital mortality when associated with Pseudomonas aeruginosa biofilms. After validating the biosafety of an attenuated M. pneumoniae chassis in mice, we introduced four transgenes in the chromosome by transposition, to implement bactericidal and biofilm degradation activities. We show that this engineered strain has high efficacy against an acute P. aeruginosa lung infection in a mouse model. In addition, we demonstrate that the engineered strain can dissolve biofilms formed in endotracheal tubes of VAP patients and can be combined with antibiotics targeting the peptidoglycan layer to increase efficacy against gram-positive and gram-negative bacteria. We expect that our

2023-10-24 | PXD037233 | Pride

The influence of two policies of closure of the laparotomy wound in the rate of surgical site infection in colorectal cancer surgery: the New Operation trial

Project description:Study hypothesis: A decreased faecal load in the surgical wound diminished the incidence of surgical site infection. Primary outcome(s): Incidence of surgical site infection. The criteria to define surgical site infection are described by Disease Control and Prevention National Healthcare Safety Network (Spain). For the purposes of this study superficial and deep wound infections would be considered as a unique entity condition. This will be measured 30 days after the operation.

| 2413447 | ecrin-mdr-crc

Aeromonas hydrophila whole cell differential proteins

Project description:Differential protein of Aeromonas hydrophila(putative human infections)'s whole cell protein

2022-01-13 | PXD029702 | Pride

Transcription profiling of responses to TNF-alpha, IL-1beta, peptidoglycan or lipopolysaccharide (TLR2/4 agonists) evaluated at 4 hrs in peripheral blood monocytes (PBM) from the patient bearing the IRAK4 Q293X mutation vs PBM from 5 healthy individuals

Project description:IL-1R associated kinase-4 (IRAK4) is a key enzyme required for activation of the common Toll-like Receptor (TLR) signaling cascade, which results in the transcription of inflammatory and immunity genes. IRAK-4 deficiency has recently been described as a rare form of innate immunodeficiency. Patients present with pyogenic bacterial infections and bacteraemia, particularly with Gram+ Streptococcus pneumoniae, and isolated PBMC from these patients fail to produce inflammatory cytokines in response to TLR agonists. We embarked on this study for several purposes: (1) to identify defective gene response resulting from IRAK4-deficiency that are responsible for the patients' susceptibility to infection by particular bacteria (2) to identify genetic responses that confer relatively normal immunity in these patients despite having a defect in such a critical component of the innate immune system (3) to gain understanding of the transcriptional regulation of inflammatory genes (4) to gain insight into TLR signal transduction pathways, in particular, the role of IRAK4 in the TLR2 and TLR4 pathways initiated by Gram+ and Gram- bacterial components respectively. Transcriptional responses to TNF-alpha, IL-1beta, peptidoglycan or lipopolysaccharide (TLR2/4 agonists) were evaluated at 4 hrs in peripheral blood monocytes (PBM) from the patient bearing the IRAK4 Q293X mutation compared to PBM from 5 healthy individuals.

2010-05-19 | E-FPMI-7 | biostudies-arrayexpress

RNAseq transcriptome analysis of K. pneumoniae MS6671 and E. coli MS8345 treated with PBT2

Project description:The emergence of colistin resistance in carbapenem-resistant and extended-spectrum ß-lactamase (ESBL)-producing bacteria is a significant threat to human health, and new treatment strategies are urgently required. Here we investigated the ability of the safe-for-human use ionophore PBT2 to restore antibiotic sensitivity in several polymyxin-resistant, ESBL-producing, carbapenem resistant Gram-negative human pathogens. PBT2 was observed to resensitize Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including a ‘next generation’ polymyxin derivative, FADDI-287. To gain additional insight into the potential mechanism of action of PBT2, we analyzed the transcriptome of K. pneumoniae and E. coli in the presence of sub-inhibitory concentrations of PBT2. Treatment with PBT2 was associated with multiple stress responses in both K. pneumoniae and E. coli. Significant changes in the transcription of transition metal ion homeostasis genes were observed in both strains.

2019-06-13 | GSE132637 | GEO

RNAseq transcriptome analysis of Streptococcus pneumoniae 23F treated with PBT2 and zinc

Project description:Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multi-drug resistance exceeding 80% and 40%, respectively. The innate immune response uses various chemical insults to control infection, including metal stress mediated by localized changes in zinc abundance. Here, we characterized the impact of S. pneumoniae zinc intoxication revealing disruptions in central carbon metabolism, lipid biogenesis and peptidoglycan biosynthesis. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human use ionophore PBT2. PBT2 rendered wild-type S. pneumoniae strains sensitive to a range of antibiotics.

2021-10-01 | GSE160372 | GEO

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