Molecular Mechanisms Involved in Pseudomonas aeruginosa Bacteremia

Pont, Stéphane; Janet-Maitre, Manon; Faudry, Eric; Cretin, François; Attrée, Ina

doi:10.1007/978-3-031-08491-1_12

Cited by 9 publications

(5 citation statements)

References 186 publications

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“…A leading hypothesis of why they are so successful is their ability to survive in the environment and in the host focuses on metabolic adaptation (71). However, A. baumannii and P. aeruginosa are also environmental pathogens capable of successfully colonizing the bloodstream but on the other hand are strict aerobes (72, 73). Metabolic flexibility may be beneficial in that they can transition between metabolic pathways during infection, or it may perhaps refer to the use of different pathways during infection altogether.…”

Section: Discussionmentioning

confidence: 99%

Fitness Factor Genes Conserved within the Multi-species Core Genome of Gram-negative Enterobacterales Species Contribute to Bacteremia Pathogenesis

Mobley,

Anderson,

Moricz

et al. 2024

Preprint

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There is a critical gap in knowledge about how Gram-negative bacterial pathogens, using survival strategies developed for other niches, cause lethal bacteremia. Facultative anaerobic species of the Enterobacterales order are the most common cause of Gram-negative bacteremia, including Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Citrobacter freundii, and Enterobacter hormaechei. Bacteremia often leads to sepsis, a life-threatening organ dysfunction resulting from an unregulated immune response to infection. Despite a lack of specialization for this host environment, Gram-negative pathogens cause nearly half of bacteremia cases annually. Based on our existing Tn-Seq fitness factor data from a murine model of bacteremia combined with comparative genomics of the five Enterobacterales species above, we prioritized 18 conserved fitness genes or operons for further characterization. Each mutant in each species was used to cochallenge C57BL/6 mice via tail vein injection along with the respective wild-type strain to determine competitive indices for each fitness gene or operon. Among the five species, we found three fitness factor genes, that when mutated, attenuated the mutant for all species in the spleen and liver (tatC, ruvA, gmhB). Nine additional fitness factor genes or operons were validated as outcompeted by wild-type in three or four bacterial species in the spleen (xerC, wzxE, arcA, prc, apaGH, atpG, lpdA, ubiH, aroC). Overall, 17 of 18 fitness factor mutants were attenuated in at least one species in the spleen or liver. Together, these findings allow for the development of a model of bacteremia pathogenesis that may include future targets of therapy against bloodstream infections.

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Section: Discussionmentioning

confidence: 99%

Fitness Factor Genes Conserved within the Multi-species Core Genome of Gram-negative Enterobacterales Species Contribute to Bacteremia Pathogenesis

Mobley,

Anderson,

Moricz

et al. 2024

Preprint

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“…Furthermore, using phenotypic assays, we tested the effect of our compounds on the activity and production of various virulence traits, such as proteases, elastase, pyocyanin, and extracellular DNA in P. aeruginosa PA14. Many extracellular enzymes with proteolytic activity are regulated by Las and Rhl circuits, including the 33-kDa elastase B being involved in the pathogenesis by acting on many substrates, e.g., elastin, collagen types II and IV, fibronectin, and immunoglobulin A, thereby degrading mucosal and connective tissues and preventing bacterial clearance ( Pont et al, 2022 ; Tummler, 2022 ). Pseudomonas aeruginosa also secretes pyocyanin, which is a blue–green-colored phenazine, redox-active, toxic secondary metabolite.…”

Section: Discussionmentioning

confidence: 99%

“…As a human opportunistic pathogen, it is one of the leading causes of nosocomial severe infections located in various host tissues, particularly in patients with impaired immunity and compromised natural barriers. If not properly eradicated during acute illnesses, P. aeruginosa can establish chronic conditions that are even more difficult to treat ( Pont et al, 2022 ; Tummler, 2022 ). This is partly due because bacteria create and live as a biofilm, i.e., a small ecosystem associated with a surface and embedded in a self-producing matrix of macromolecules.…”

Section: Introductionmentioning

confidence: 99%

“…This biofilm provides a sustainable community with highly coordinated production of virulent determinants and increased resistance to the immune system and drugs ( Hoiby et al, 2010 ; Breidenstein et al, 2011 ; Poole, 2011 ). Moreover, P. aeruginosa is equipped with a broad array of virulence traits and sophisticated molecular mechanisms that allow the bacteria to accommodate their lifestyle, manipulate host–pathogen interactions, and escape host defense ( Pont et al, 2022 ; Tummler, 2022 ). The plasticity of the P. aeruginosa genome, supported by global regulatory networks, is a central feature in the pathogen’s ability to adapt and survive within the host.…”

Section: Introductionmentioning

confidence: 99%

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Modified N-acyl-L-homoserine lactone compounds abrogate Las-dependent quorum-sensing response in human pathogen Pseudomonas aeruginosa

Ballante,

Turkina,

Ntzouni

et al. 2023

Front. Mol. Biosci.

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Quorum sensing (QS) is a mode of cell–cell communication that bacteria use to sense population density and orchestrate collective behaviors. The common opportunistic human pathogen Pseudomonas aeruginosa employs QS to regulate a large set of genes involved in virulence and host–pathogen interactions. The Las circuit positioned on the top of the QS hierarchy in P. aeruginosa makes use of N-acyl-L-homoserine lactones (AHLs) as signal molecules, like N-3-oxo-dodecanoyl-L-homoserine lactone (3O-C12-HSL). Disabling QS circuits by certain small-molecule compounds, known as quorum-sensing inhibitors (QSIs), has been proposed as a strategy to attenuate bacterial pathogenicity. In this study, four new AHL analogs were designed by incorporating a tert-butoxycarbonyl Boc group in amide and β-keto (3-oxo) moiety. Compounds were evaluated on a molecular and phenotypic basis as a QSI using the screening strategy linked to the assignment of the Las QS system in P. aeruginosa. Using a LasR-based bioreporter, we found that the compounds decreased LasR-controlled light activity and competed efficiently with natural 3O-C12-HSL. The compounds reduced the production of the cognate 3O-C12-HSL and certain virulence traits, like total protease activity, elastase activity, pyocyanin production, and extracellular DNA release. Furthermore, a quantitative proteomic approach was used to study the effect of the compounds on QS-regulated extracellular proteins. Among the four compounds tested, one of them showed the most significant difference in the appearance of the 3O-C12-HSL-responsive reference proteins related to QS communication and virulence, i.e., a distinct activity as a QSI. Moreover, by combining experimental data with computational chemistry, we addressed the effect of LasR protein flexibility on docking precision and assessed the advantage of using a multi-conformational docking procedure for binding mode prediction of LasR modulators. Thus, the four new AHL compounds were tested for their interaction with the AHL-binding site in LasR to identify the key interferences with the activity of LasR. Our study provides further insight into molecular features that are required for small-molecule modulation of LasR-dependent QS communication in P. aeruginosa. This should facilitate rational design of the next generation of antivirulence tools to study and manipulate QS-controlled fitness in bacteria and, thereby, handle bacterial infections in a new way.

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“…Pseudomonas aeruginosa uses a biofilm-like matrix for the transmigration process and uses multiple approaches to gain entry into the host cells, such as T2SS, quorum sensing, T3SS, and chemicals like N-(3-oxododecanoyl) L-homoserine lactone. The combined use of toxin and protease hamper the cell junction integrity allowing pathogen entry into the host cells (reviewed by Golovkine et al 2018 ; Qin et al 2022 ; Pont et al 2022 ). To cross the host blood barrier, Neisseria meningitides disrupt the endothelial permeability and it was proposed that N. meningitides recruit proteins involved in the formation and stabilization of adherens and tight junction into the cortical plaques, which is a molecular complex formed under the bacterial colonies, leading to the opening of intercellular cell junction (Coureuil et al 2012 ).…”

Section: Disrupters Of Epithelial Junction During Infectionmentioning

confidence: 99%

Cleavage of cell junction proteins as a host invasion strategy in leptospirosis

Kumari,

Yadav,

Sarkar

et al. 2024

Appl Microbiol Biotechnol

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Infection and invasion are the prerequisites for developing the disease symptoms in a host. While the probable mechanism of host invasion and pathogenesis is known in many pathogens, very little information is available on Leptospira invasion/pathogenesis. For causing systemic infection Leptospira must transmigrate across epithelial barriers, which is the most critical and challenging step. Extracellular and membrane-bound proteases play a crucial role in the invasion process. An extensive search for the proteins experimentally proven to be involved in the invasion process through cell junction cleavage in other pathogens has resulted in identifying 26 proteins. The similarity searches on the Leptospira genome for counterparts of these 26 pathogenesis-related proteins identified at least 12 probable coding sequences. The proteins were either extracellular or membrane-bound with a proteolytic domain to cleave the cell junction proteins. This review will emphasize our current understanding of the pathogenic aspects of host cell junction-pathogenic protein interactions involved in the invasion process. Further, potential candidate proteins with cell junction cleavage properties that may be exploited in the diagnostic/therapeutic aspects of leptospirosis will also be discussed. Key points • The review focussed on the cell junction cleavage proteins in bacterial pathogenesis • Cell junction disruptors from Leptospira genome are identified using bioinformatics • The review provides insights into the therapeutic/diagnostic interventions possible

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Molecular Mechanisms Involved in Pseudomonas aeruginosa Bacteremia

Cited by 9 publications

References 186 publications

Fitness Factor Genes Conserved within the Multi-species Core Genome of Gram-negative Enterobacterales Species Contribute to Bacteremia Pathogenesis

Fitness Factor Genes Conserved within the Multi-species Core Genome of Gram-negative Enterobacterales Species Contribute to Bacteremia Pathogenesis

Modified N-acyl-L-homoserine lactone compounds abrogate Las-dependent quorum-sensing response in human pathogen Pseudomonas aeruginosa

Cleavage of cell junction proteins as a host invasion strategy in leptospirosis

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