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Cell Metabolism Oct 2023Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response;...
Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.
Topics: Mice; Animals; Pseudomonas aeruginosa; Lipopolysaccharides; Lung; Inflammation; Ketone Bodies
PubMed: 37793346
DOI: 10.1016/j.cmet.2023.09.001 -
Nature Microbiology Aug 2023Efficient colonization of mucosal surfaces is essential for opportunistic pathogens like Pseudomonas aeruginosa, but how bacteria collectively and individually adapt to...
Efficient colonization of mucosal surfaces is essential for opportunistic pathogens like Pseudomonas aeruginosa, but how bacteria collectively and individually adapt to optimize adherence, virulence and dispersal is largely unclear. Here we identified a stochastic genetic switch, hecR-hecE, which is expressed bimodally and generates functionally distinct bacterial subpopulations to balance P. aeruginosa growth and dispersal on surfaces. HecE inhibits the phosphodiesterase BifA and stimulates the diguanylate cyclase WspR to increase c-di-GMP second messenger levels and promote surface colonization in a subpopulation of cells; low-level HecE-expressing cells disperse. The fraction of HecE cells is tuned by different stress factors and determines the balance between biofilm formation and long-range cell dispersal of surface-grown communities. We also demonstrate that the HecE pathway represents a druggable target to effectively counter P. aeruginosa surface colonization. Exposing such binary states opens up new ways to control mucosal infections by a major human pathogen.
Topics: Pseudomonas aeruginosa; Bacterial Adhesion; Biofilms
PubMed: 37291227
DOI: 10.1038/s41564-023-01403-0 -
Cell Nov 2023Drug-resistant Pseudomonas aeruginosa (PA) poses an emerging threat to human health with urgent need for alternative therapeutic approaches. Here, we deciphered the B...
Drug-resistant Pseudomonas aeruginosa (PA) poses an emerging threat to human health with urgent need for alternative therapeutic approaches. Here, we deciphered the B cell and antibody response to the virulence-associated type III secretion system (T3SS) in a cohort of patients chronically infected with PA. Single-cell analytics revealed a diverse B cell receptor repertoire directed against the T3SS needle-tip protein PcrV, enabling the production of monoclonal antibodies (mAbs) abrogating T3SS-mediated cytotoxicity. Mechanistic studies involving cryoelectron microscopy identified a surface-exposed C-terminal PcrV epitope as the target of highly neutralizing mAbs with broad activity against drug-resistant PA isolates. These anti-PcrV mAbs were as effective as treatment with conventional antibiotics in vivo. Our study reveals that chronically infected patients represent a source of neutralizing antibodies, which can be exploited as therapeutics against PA.
Topics: Humans; Antibodies, Bacterial; Cryoelectron Microscopy; Immunoglobulins; Pseudomonas aeruginosa; Antibodies, Neutralizing; Pseudomonas Infections
PubMed: 37918395
DOI: 10.1016/j.cell.2023.10.002 -
Biometals : An International Journal on... Aug 2023In the genus Pseudomonas, zinc homeostasis is mediated by a complete set of import and export systems, whose expression is precisely controlled by three transcriptional... (Review)
Review
In the genus Pseudomonas, zinc homeostasis is mediated by a complete set of import and export systems, whose expression is precisely controlled by three transcriptional regulators: Zur, CzcR and CadR. In this review, we describe in detail our current knowledge of these systems, their regulation, and the biological significance of zinc homeostasis, taking Pseudomonas aeruginosa as our paradigm. Moreover, significant parts of this overview are dedicated to highlight interactions and cross-regulations between zinc and copper import/export systems, and to shed light, through a review of the literature and comparative genomics, on differences in gene complement and function across the whole Pseudomonas genus. The impact and importance of zinc homeostasis in Pseudomonas and beyond will be discussed throughout this review.
Topics: Pseudomonas; Zinc; Homeostasis; Pseudomonas aeruginosa; Copper; Bacterial Proteins; Gene Expression Regulation, Bacterial
PubMed: 36472780
DOI: 10.1007/s10534-022-00475-5 -
Current Opinion in Chemical Biology Feb 2024Exopolysaccharides are produced and excreted by bacteria in the generation of biofilms to provide a protective environment. These polysaccharides are generally generated... (Review)
Review
Exopolysaccharides are produced and excreted by bacteria in the generation of biofilms to provide a protective environment. These polysaccharides are generally generated as heterogeneous polymers of varying length, featuring diverse substitution patterns. To obtain well-defined fragments of these polysaccharides, organic synthesis often is the method of choice, as it allows for full control over chain length and the installation of a pre-determined substitution pattern. This review presents several recent syntheses of exopolysaccharide fragments of Pseudomonas aeruginosa and Staphylococcus aureus and illustrates how these have been used to study biosynthesis enzymes and generate synthetic glycoconjugate vaccines.
Topics: Polysaccharides, Bacterial; Biofilms; Pseudomonas aeruginosa
PubMed: 38134611
DOI: 10.1016/j.cbpa.2023.102418 -
Viruses Oct 2023Half a century has passed since the discovery of Pseudomonas phage phi6, the first enveloped dsRNA bacteriophage to be isolated. It remained the sole known dsRNA phage... (Review)
Review
Half a century has passed since the discovery of Pseudomonas phage phi6, the first enveloped dsRNA bacteriophage to be isolated. It remained the sole known dsRNA phage for a quarter of a century and the only recognised member of the family until the year 2018. After the initial discovery of phi6, additional dsRNA phages have been isolated from globally distant locations and identified in metatranscriptomic datasets, suggesting that this virus type is more ubiquitous in nature than previously acknowledged. Most identified dsRNA phages infect strains and utilise either pilus or lipopolysaccharide components of the host as the primary receptor. In addition to the receptor-mediated strictly lytic lifestyle, an alternative persistent infection strategy has been described for some dsRNA phages. To date, complete genome sequences of fourteen dsRNA phage isolates are available. Despite the high sequence diversity, similar sets of genes can typically be found in the genomes of dsRNA phages, suggesting shared evolutionary trajectories. This review provides a brief overview of the recognised members of the virus family and related dsRNA phage isolates, outlines the current classification of dsRNA phages, and discusses their relationships with eukaryotic RNA viruses.
Topics: Bacteriophages; Pseudomonas Phages; Pseudomonas; Genome, Viral
PubMed: 38005832
DOI: 10.3390/v15112154 -
Ugeskrift For Laeger Jan 2024We present a case report detailing therapeutic application of two lytic antipseudomonal bacteriophages to treat a chronic relapsing Pseudomonas aeruginosa infection of a...
We present a case report detailing therapeutic application of two lytic antipseudomonal bacteriophages to treat a chronic relapsing Pseudomonas aeruginosa infection of a prosthetic aortic graft. As there are currently no Danish laboratories offering phages for clinical therapy, and this case, to our knowledge represents the first applied phage therapy in Denmark, the practical and regulatory aspects of offering this treatment option in Denmark is briefly reviewed along with the clinical case.
Topics: Humans; Bacteriophages; Pseudomonas; Pseudomonas Phages; Blood Vessel Prosthesis; Pseudomonas aeruginosa
PubMed: 38305316
DOI: 10.61409/V09230617 -
Trends in Microbiology Aug 2023Bacillus and Pseudomonas ubiquitously occur in natural environments and are two of the most intensively studied bacterial genera in the soil. They are often coisolated... (Review)
Review
Bacillus and Pseudomonas ubiquitously occur in natural environments and are two of the most intensively studied bacterial genera in the soil. They are often coisolated from environmental samples, and as a result, several studies have experimentally cocultured bacilli and pseudomonads to obtain emergent properties. Even so, the general interaction between members of these genera is virtually unknown. In the past decade, data on interspecies interactions between natural isolates of Bacillus and Pseudomonas has become more detailed, and now, molecular studies permit mapping of the mechanisms behind their pairwise ecology. This review addresses the current knowledge about microbe-microbe interactions between strains of Bacillus and Pseudomonas and discusses how we can attempt to generalize the interaction on a taxonomic and molecular level.
Topics: Pseudomonas; Bacillus; Soil; Soil Microbiology; Bacteria
PubMed: 36878770
DOI: 10.1016/j.tim.2023.02.003 -
Frontiers in Cellular and Infection... 2023Bacterial keratitis (bacterial infection of the cornea) is a major cause of vision loss worldwide. Given the rapid and aggressive nature of the disease, immediate... (Review)
Review
Bacterial keratitis (bacterial infection of the cornea) is a major cause of vision loss worldwide. Given the rapid and aggressive nature of the disease, immediate broad-spectrum antibiotics are essential to adequately treat this disease. However, rising antibiotic resistance continues to accelerate, rendering many commonly used therapeutics increasingly ineffective. As such, there is a significant effort to understand the basic pathogenesis of common causative organisms implicated in keratitis in part, to fuel the development of novel therapies to treat this blinding disease. This review explores two common causes of bacterial keratitis, and , with regards to the bacterial mediators of virulence as well as novel therapies on the horizon.
Topics: Humans; Staphylococcus aureus; Pseudomonas aeruginosa; Staphylococcal Infections; Keratitis; Pseudomonas Infections; Eye Infections, Bacterial
PubMed: 37671149
DOI: 10.3389/fcimb.2023.1250257 -
The New Phytologist Sep 2023Some nucleotide-binding and leucine-rich repeat receptors (NLRs) indirectly detect pathogen effectors by monitoring their host targets. In Arabidopsis thaliana, RIN4 is...
Some nucleotide-binding and leucine-rich repeat receptors (NLRs) indirectly detect pathogen effectors by monitoring their host targets. In Arabidopsis thaliana, RIN4 is targeted by multiple sequence-unrelated effectors and activates immune responses mediated by RPM1 and RPS2. These effectors trigger cell death in Nicotiana benthamiana, but the corresponding NLRs have yet not been identified. To identify N. benthamiana NLRs (NbNLRs) that recognize Arabidopsis RIN4-targeting effectors, we conducted a rapid reverse genetic screen using an NbNLR VIGS library. We identified that the N. benthamiana homolog of Ptr1 (Pseudomonas tomato race 1) recognizes the Pseudomonas effectors AvrRpt2, AvrRpm1, and AvrB. We demonstrated that recognition of the Xanthomonas effector AvrBsT and the Pseudomonas effector HopZ5 is conferred independently by the N. benthamiana homolog of Ptr1 and ZAR1. Interestingly, the recognition of HopZ5 and AvrBsT is contributed unequally by Ptr1 and ZAR1 in N. benthamiana and Capsicum annuum. In addition, we showed that the RLCK XII family protein JIM2 is required for the NbZAR1-dependent recognition of AvrBsT and HopZ5. The recognition of sequence-unrelated effectors by NbPtr1 and NbZAR1 provides an additional example of convergently evolved effector recognition. Identification of key components involved in Ptr1 and ZAR1-mediated immunity could reveal unique mechanisms of expanded effector recognition.
Topics: Arabidopsis; Proteins; Bacteria; Carrier Proteins; Pseudomonas; Receptors, Immunologic; Bacterial Proteins; Pseudomonas syringae; Plant Diseases; Arabidopsis Proteins; Intracellular Signaling Peptides and Proteins
PubMed: 37334551
DOI: 10.1111/nph.19073