18 results on '"Couzon F"'
Search Results
2. Potential role of Mercury pollutants in the success of Methicillin-Resistant Staphylococcus aureus USA300 in Latin America
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Gustave, C. A., primary, Rasigade, J.P., additional, Martins-Simões, Patricia, additional, Couzon, F., additional, Bourg, Chloe, additional, Tristan, Anne, additional, Laurent, Frédéric, additional, Wirth, T., additional, and Vandenesch, F., additional
- Published
- 2020
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3. Optimisation des doses en radio-pédiatrie lors des cystographies et TOGD
- Author
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Couzon, F., primary, Gulyayeva Nsair, L., additional, and Russel Robillard, A.S., additional
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- 2018
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4. RlmQ: a newly discovered rRNA modification enzyme bridging RNA modification and virulence traits in Staphylococcus aureus .
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Bahena-Ceron R, Teixeira C, Ponce JRJ, Wolff P, Couzon F, François P, Klaholz BP, Vandenesch F, Romby P, Moreau K, and Marzi S
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- Staphylococcus aureus genetics, RNA, Virulence genetics, RNA, Ribosomal, 23S genetics, Methyltransferases genetics, Escherichia coli, Escherichia coli Proteins genetics
- Abstract
rRNA modifications play crucial roles in fine-tuning the delicate balance between translation speed and accuracy, yet the underlying mechanisms remain elusive. Comparative analyses of the rRNA modifications in taxonomically distant bacteria could help define their general, as well as species-specific, roles. In this study, we identified a new methyltransferase, RlmQ, in Staphylococcus aureus responsible for the Gram-positive specific m
7 G2601, which is not modified in Escherichia coli (G2574). We also demonstrate the absence of methylation on C1989, equivalent to E. coli C1962, which is methylated at position 5 by the Gram-negative specific RlmI methyltransferase, a paralog of RlmQ. Both modifications ( S. aureus m7 G2601 and E. coli m5 C1962) are situated within the same tRNA accommodation corridor, hinting at a potential shared function in translation. Inactivation of S. aureus rlmQ causes the loss of methylation at G2601 and significantly impacts growth, cytotoxicity, and biofilm formation. These findings unravel the intricate connections between rRNA modifications, translation, and virulence in pathogenic Gram-positive bacteria., (© 2024 Bahena-Ceron et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)- Published
- 2024
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5. Complex Regulation of Gamma-Hemolysin Expression Impacts Staphylococcus aureus Virulence.
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Pivard M, Caldelari I, Brun V, Croisier D, Jaquinod M, Anzala N, Gilquin B, Teixeira C, Benito Y, Couzon F, Romby P, Moreau K, and Vandenesch F
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- Animals, Rabbits, Leukocidins genetics, Leukocidins metabolism, Leukocidins pharmacology, Hemolysin Proteins genetics, Hemolysin Proteins metabolism, Virulence genetics, Exotoxins genetics, Exotoxins metabolism, Virulence Factors genetics, Virulence Factors metabolism, Staphylococcus aureus metabolism, Staphylococcal Infections
- Abstract
Staphylococcus aureus gamma-hemolysin CB (HlgCB) is a core-genome-encoded pore-forming toxin that targets the C5a receptor, similar to the phage-encoded Panton-Valentine leucocidin (PVL). Absolute quantification by mass spectrometry of HlgCB in 39 community-acquired pneumonia (CAP) isolates showed considerable variations in the HlgC and HlgB yields between isolates. Moreover, although HlgC and HlgB are encoded on a single operon, their levels were dissociated in 10% of the clinical strains studied. To decipher the molecular basis for the variation in hlgCB expression and protein production among strains, different regulation levels were analyzed in representative clinical isolates and reference strains. Both the HlgCB level and the HlgC/HlgB ratio were found to depend on hlgC promoter activity and mRNA processing and translation. Strikingly, only one single nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of hlgCB mRNA strongly impaired hlgC translation in the USA300 strain, leading to a strong decrease in the level of HlgC but not in HlgB. Finally, we found that high levels of HlgCB synthesis led to mortality in a rabbit model of pneumonia, correlated with the implication of the role of HlgCB in severe S. aureus CAP. Taken together, this work illustrates the complexity of virulence factor expression in clinical strains and demonstrates a butterfly effect where subtle genomic variations have a major impact on phenotype and virulence. IMPORTANCE S. aureus virulence in pneumonia results in its ability to produce several virulence factors, including the leucocidin PVL. Here, we demonstrate that HlgCB, another leucocidin, which targets the same receptors as PVL, highly contributes to S. aureus virulence in pvl -negative strains. In addition, considerable variations in HlgCB quantities are observed among clinical isolates from patients with CAP. Biomolecular analyses have revealed that a few SNPs in the promoter sequences and only one SNP in the 5' UTR of hlgCB mRNA induce the differential expression of hlgCB , drastically impacting hlgC mRNA translation. This work illustrates the subtlety of regulatory mechanisms in bacteria, especially the sometimes major effects on phenotypes of single nucleotide variation in noncoding regions., Competing Interests: The authors declare no conflict of interest.
- Published
- 2023
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6. Targeted proteomics links virulence factor expression with clinical severity in staphylococcal pneumonia.
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Pivard M, Bastien S, Macavei I, Mouton N, Rasigade JP, Couzon F, Youenou B, Tristan A, Carrière R, Moreau K, Lemoine J, and Vandenesch F
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- Humans, Staphylococcus aureus, Virulence Factors genetics, Hemoptysis, Proteomics, Exotoxins genetics, Staphylococcus, Leukocidins genetics, Pneumonia, Staphylococcal microbiology, Staphylococcal Infections microbiology, Community-Acquired Infections microbiology, Methicillin-Resistant Staphylococcus aureus genetics
- Abstract
Introduction: The bacterial pathogen Staphylococcus aureus harbors numerous virulence factors that impact infection severity. Beyond virulence gene presence or absence, the expression level of virulence proteins is known to vary across S. aureus lineages and isolates. However, the impact of expression level on severity is poorly understood due to the lack of high-throughput quantification methods of virulence proteins., Methods: We present a targeted proteomic approach able to monitor 42 staphylococcal proteins in a single experiment. Using this approach, we compared the quantitative virulomes of 136 S. aureus isolates from a nationwide cohort of French patients with severe community-acquired staphylococcal pneumonia, all requiring intensive care. We used multivariable regression models adjusted for patient baseline health (Charlson comorbidity score) to identify the virulence factors whose in vitro expression level predicted pneumonia severity markers, namely leukopenia and hemoptysis, as well as patient survival., Results: We found that leukopenia was predicted by higher expression of HlgB, Nuc, and Tsst-1 and lower expression of BlaI and HlgC, while hemoptysis was predicted by higher expression of BlaZ and HlgB and lower expression of HlgC. Strikingly, mortality was independently predicted in a dose-dependent fashion by a single phage-encoded virulence factor, the Panton-Valentine leucocidin (PVL), both in logistic (OR 1.28; 95%CI[1.02;1.60]) and survival (HR 1.15; 95%CI[1.02;1.30]) regression models., Discussion: These findings demonstrate that the in vitro expression level of virulence factors can be correlated with infection severity using targeted proteomics, a method that may be adapted to other bacterial pathogens., Competing Interests: FV and JPR report research funding outside the scope of the present study by bioMérieux. FV reports two patents pending in antimicrobial resistance detection. FV, JL and J-PR report shares in Weezion. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Pivard, Bastien, Macavei, Mouton, Rasigade, Couzon, Youenou, Tristan, Carrière, Moreau, Lemoine and Vandenesch.)
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- 2023
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7. All Staphylococcus aureus bacteraemia-inducing strains can cause infective endocarditis: Results of GWAS and experimental animal studies.
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Bastien S, Meyers S, Salgado-Pabón W, Giulieri SG, Rasigade JP, Liesenborghs L, Kinney KJ, Couzon F, Martins-Simoes P, Moing VL, Duval X, Holmes NE, Bruun NE, Skov R, Howden BP, Fowler VG Jr, Verhamme P, Andersen PS, Bouchiat C, Moreau K, and Vandenesch F
- Subjects
- Animals, Rabbits, Mice, Genome-Wide Association Study, Staphylococcus aureus genetics, Bacteremia microbiology, Staphylococcal Infections microbiology, Endocarditis, Bacterial microbiology, Endocarditis microbiology
- Abstract
Objectives: We aimed at determining whether specific S. aureus strains cause infective endocarditis (IE) in the course of Staphylococcus aureus bacteraemia (SAB)., Methods: A genome-wide association study (GWAS) including 924 S. aureus genomes from IE (274) and non-IE (650) SAB patients from international cohorts was conducted, and a subset of strains was tested with two experimental animal models of IE, one investigating the early step of bacterial adhesion to inflamed mice valves, the second evaluating the local and systemic developmental process of IE on mechanically-damaged rabbit valves., Results: The genetic profile of S. aureus IE and non-IE SAB strains did not differ when considering single nucleotide polymorphisms, coding sequences, and k-mers analysed in GWAS. In the murine inflammation-induced IE model, no difference was observed between IE and non-IE SAB strains both in terms of adhesion to the cardiac valves and in the propensity to cause IE; in the mechanical IE-induced rabbit model, there was no difference between IE and non-IE SAB strains regarding the vegetation size and CFU., Conclusion: All strains of S. aureus isolated from SAB patients must be considered as capable of causing this common and lethal infection once they have accessed the bloodstream., Competing Interests: Declaration of Competing Interest FV reports research funding outside the scope of the present study by bioMérieux, two patents pending in antimicrobial resistance detection and shares in Weezion. VGF reports personal fees from Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny, Amphliphi Biosciences. Integrated Biotherapeutics; C3J, grants from NIH, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Basilea, Janssen, from Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm, Royalties from UpToDate; and a patent pending in sepsis diagnostics., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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8. Correction to: National dose reference levels in computed tomography-guided interventional procedures-a proposal.
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Greffier J, Ferretti G, Rousseau J, Andreani O, Alonso E, Rauch A, Gillet R, Le Roy J, Cabrol-Faivre L, Douane F, David A, Henry S, Jacques T, Stefanovic X, Decoux E, Lafay F, Pilleul F, Couzon F, Boutet C, Woerly B, Baur P, Sans N, Faruch M, Moussier-Lherm A, Tselikas L, Jacquier A, Bigand E, Pessis E, Teriitehau C, Magnier F, Cassagnes L, Haberlay M, Boutteau D, De Kerviler E, Majorel-Gouthain C, Defez D, Vuillod A, Rouviere O, Hennequin L, Fohlen A, Alwan R, Malakhia A, Aubry S, Dohan A, Eresue-Bony M, Gautier R, Dal R, Dabli D, Hebert T, Kovacs R, Hadid-Beurrier L, Bousson V, Potel M, Barbotteau Y, Michel C, Habib-Geryes B, André M, Arnaud T, Bestion N, Ernst O, Monfraix S, Brillet PY, Guiu B, Boussel L, Demonchy M, Beregi JP, and Frandon J
- Abstract
The original version of this article, published on 02 May 2020, unfortunately contained a mistake.
- Published
- 2020
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9. National dose reference levels in computed tomography-guided interventional procedures-a proposal.
- Author
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Greffier J, Ferretti G, Rousseau J, Andreani O, Alonso E, Rauch A, Gillet R, Le Roy J, Cabrol-Faivre L, Douane F, David A, Henry S, Jacques T, Stefanovic X, Decoux E, Lafay F, Pilleul F, Couzon F, Boutet C, Woerly B, Baur P, Sans N, Faruch M, Moussier-Lherm A, Tselikas L, Jacquier A, Bigand E, Pessis E, Teriitehau C, Magnier F, Cassagnes L, Haberlay M, Boutteau D, De Kerviler E, Majorel-Gouthain C, Defez D, Vuillod A, Rouviere O, Hennequin L, Fohlen A, Alwan R, Malakhia A, Aubry S, Dohan A, Eresue-Bony M, Gautier R, Dal R, Dabli D, Hebert T, Kovacs R, Hadid-Beurrier L, Bousson V, Potel M, Barbotteau Y, Michel C, Habib-Geryes B, André M, Arnaud T, Bestion N, Ernst O, Monfraix S, Brillet PY, Guiu B, Boussel L, Demonchy M, Beregi JP, and Frandon J
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biopsy, Female, Fluoroscopy methods, France, Humans, Male, Middle Aged, Radiography, Interventional methods, Reproducibility of Results, Retrospective Studies, Spine, Surveys and Questionnaires, Tomography, X-Ray Computed methods, Vertebroplasty, Young Adult, Radiation Dosage, Radiography, Interventional standards, Reference Values, Tomography, X-Ray Computed standards
- Abstract
Objectives: To establish national reference levels (RLs) in interventional procedures under CT guidance as required by the 2013/59/Euratom European Directive., Methods: Seventeen categories of interventional procedures in thoracic, abdominopelvic, and osteoarticular specialties (percutaneous infiltration, vertebroplasty, biopsy, drainage, tumor destruction) were analyzed. Total dose length product (DLP), number of helical acquisitions (NH), and total DLP for helical, sequential, or fluoroscopic acquisitions were recorded for 10 to 20 patients per procedure at each center. RLs were calculated as the 3rd quartiles of the distributions and target values for optimization process (TVOs) as the median. RLs and TVOs were compared with previously published studies., Results: Results on 5001 procedures from 49 centers confirmed the great variability in patient dose for the same category of procedures. RLs were proposed for the DLPs and NHs in the seventeen categories. RLs in terms of DLP and NH were 375 mGy.cm and 2 NH for spinal or peri-spinal infiltration, 1630 mGy.cm and 3 NH for vertebroplasty, 845 mGy.cm and 4 NH for biopsy, 1950 mGy.cm and 8 NH for destruction of tumors, and 1090 mGy.cm and 5 NH for drainage. DLP and NH increased with the complexity of procedures., Conclusions: This study was the first nationwide multicentric survey to propose RLs for interventional procedures under CT guidance. Heterogeneity of practice in centers were found with different levels of patient doses for the same procedure. The proposed RLs will allow imaging departments to benchmark their practice with others and optimize their protocols., Key Points: • National reference levels are proposed for 17 categories of interventional procedures under CT guidance. • Reference levels are useful for benchmarking practices and optimizing protocols. • Reference levels are proposed for dose length product and the number of helical acquisitions.
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- 2020
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10. Human Genetic Susceptibility to Native Valve Staphylococcus aureus Endocarditis in Patients With S. aureus Bacteremia: Genome-Wide Association Study.
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Moreau K, Clemenceau A, Le Moing V, Messika-Zeitoun D, Andersen PS, Bruun NE, Skov RL, Couzon F, Bouchiat C, Erpelding ML, van Belkum A, Bossé Y, Duval X, and Vandenesch F
- Abstract
Staphylococcus aureus infective endocarditis (SaIE) is a severe complication of S. aureus bacteremia (SAB) occurring in up to 22% of patients. Bacterial genetic factors and host conditions for SaIE have been intensely studied before; however, to date no study has focused on predisposing host genetic factors to SaIE. The present study aimed to identify genetic polymorphisms associated with SaIE by a Genome-Wide Association Study (GWAS) of 67 patients with definite native valve SaIE (cases) and 72 matched native valve patients with SAB but without IE (controls). All patients were enrolled in the VIRSTA cohort (Le Moing et al., 2015) study. Four single nucleotide polymorphisms (SNPs) located on chromosome 3 were associated with SaIE ( P < 1 × 10
-5 ) without reaching conventional genome-wide significance. For all, the frequency of the minor allele was lower in cases than in controls, suggesting a protective effect of the minor allele against SaIE. The same association was observed using an independent Danish verification cohort of SAB with ( n = 57) and without ( n = 123) IE. Ex vivo analysis of aortic valve tissues revealed that SaIE associated SNPs mentioned above were associated with significantly higher mRNA expression levels of SLC7A14, a predicted cationic amino acid transporter protein. Taken together, our results suggest an IE-protective effect of SNPs on chromosome 3 during the course of SAB. The effects of protective minor alleles may be mediated by increasing expression levels of SLC7A14 in valve tissues. We conclude that occurrence of SaIE may be the combination of a well-adapted bacterial genotype to a susceptible host.- Published
- 2018
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11. Phenol-Soluble Modulins Contribute to Early Sepsis Dissemination Not Late Local USA300-Osteomyelitis Severity in Rabbits.
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Davido B, Saleh-Mghir A, Laurent F, Danel C, Couzon F, Gatin L, Vandenesch F, Rasigade JP, and Crémieux AC
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- Animals, Disease Models, Animal, Rabbits, Bacterial Toxins genetics, Bacterial Toxins metabolism, Methicillin-Resistant Staphylococcus aureus genetics, Methicillin-Resistant Staphylococcus aureus metabolism, Methicillin-Resistant Staphylococcus aureus pathogenicity, Osteomyelitis genetics, Osteomyelitis metabolism, Osteomyelitis microbiology, Osteomyelitis pathology, Sepsis genetics, Sepsis metabolism, Sepsis microbiology, Sepsis pathology, Staphylococcal Infections genetics, Staphylococcal Infections metabolism, Staphylococcal Infections microbiology, Staphylococcal Infections pathology
- Abstract
Introduction: In bone and joint infections (BJIs), bacterial toxins are major virulence factors: Panton-Valentine leukocidin (PVL) expression leads to severe local damage, including bone distortion and abscesses, while α-hemolysin (Hla) production is associated with severe sepsis-related mortality. Recently, other toxins, namely phenol-soluble modulins (PSMs) expressed by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain USA300 (LAC WT) were shown to have ex vivo intracellular cytotoxic activity after S. aureus invasion of osteoblasts, but their in vivo contribution in a relatively PVL-sensitive osteomyelitis model remains poorly elucidated., Materials and Methods: We compared the outcomes of experimental rabbit osteomyelitises induced with pvl+hla+psms+ LAC WT and its isogenic Δpsm derivatives (LAC Δpsmα and LAC Δpsmαβhld) using an inoculum of 3 × 108 CFUs. Mortality, hematogenous spread (blood culture, spleen and kidney), lung and bone involvements were assessed in two groups (non-survivors of severe sepsis and survivors sacrificed on day (D) 14)., Results: Severe sepsis-related mortality tended to be lower for Δpsm derivatives (Kaplan-Meier curves, P = .06). Non-survivors' bone LAC-Δpsmα (6.9 log10 CFUs/g of bone, P = .04) or -Δpsmαβhld (6.86 log10 CFUs/g of bone, P = .014) densities were significantly higher than LAC WT (6.43 log10 CFUs/g of bone). Conversely, lung Δpsmαβhld CFUs were significantly lower than LAC WT (P = .04). LAC Δpsmα, Δpsmαβhld and WT induced similar bone damage in D14 survivors, with comparable bacterial densities (respectively: 5.89, 5.91, and 6.15 log10 CFUs/g of bone). Meanwhile, pulmonary histological scores of inflammation were significantly higher for LAC Δpsmα- and Δpsmαβhld-infected rabbits compared to LAC WT (P = .04 and .01, respectively) but with comparable lung bacterial densities., Conclusion: Our experimental results showed that deactivating PSM peptides significantly limited bacterial dissemination from bone during the early phase of infection, but did not affect local severity of USA300 rabbit osteomyelitis.
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- 2016
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12. Kineret®/IL-1ra blocks the IL-1/IL-8 inflammatory cascade during recombinant Panton Valentine Leukocidin-triggered pneumonia but not during S. aureus infection.
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Labrousse D, Perret M, Hayez D, Da Silva S, Badiou C, Couzon F, Bes M, Chavanet P, Lina G, Vandenesch F, Croisier-Bertin D, and Henry T
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- Animals, Inflammasomes drug effects, Inflammasomes immunology, Interleukin 1 Receptor Antagonist Protein therapeutic use, Macrophages drug effects, Macrophages immunology, Pneumonia, Staphylococcal etiology, Pneumonia, Staphylococcal metabolism, Rabbits, Bacterial Toxins toxicity, Exotoxins toxicity, Interleukin 1 Receptor Antagonist Protein pharmacology, Interleukin-1beta metabolism, Interleukin-8 metabolism, Leukocidins toxicity, Pneumonia, Staphylococcal drug therapy
- Abstract
Objectives: Community-acquired Staphylococcus aureus necrotizing pneumonia is a life-threatening disease. Panton Valentine Leukocidin (PVL) has been associated with necrotizing pneumonia. PVL triggers inflammasome activation in human macrophages leading to IL-1β release. IL-1β activates lung epithelial cells to release IL-8. This study aimed to assess the relevance of this inflammatory cascade in vivo and to test the potential of an IL-1 receptor antagonist (IL-1Ra/Kineret) to decrease inflammation-mediated lung injury., Methods: We used the sequential instillation of Heat-killed S. aureus and PVL or S. aureus infection to trigger necrotizing pneumonia in rabbits. In these models, we investigated inflammation in the presence or absence of IL-1Ra/Kineret., Results: We demonstrated that the presence of PVL was associated with IL-1β and IL-8 release in the lung. During PVL-mediated sterile pneumonia, Kineret/IL-1Ra reduced IL-8 production indicating the relevance of the PVL/IL-1/IL-8 cascade in vivo and the potential of Kineret/IL-1Ra to reduce lung inflammation. However, Kineret/IL-1Ra was ineffective in blocking IL-8 production during infection with S. aureus. Furthermore, treatment with Kineret increased the bacterial burden in the lung., Conclusions: Our data demonstrate PVL-dependent inflammasome activation during S.aureus pneumonia, indicate that IL-1 signaling controls bacterial burden in the lung and suggest that therapy aimed at targeting this pathway might be deleterious during pneumonia.
- Published
- 2014
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13. α-Hemolysin, not Panton-Valentine leukocidin, impacts rabbit mortality from severe sepsis with methicillin-resistant Staphylococcus aureus osteomyelitis.
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Crémieux AC, Saleh-Mghir A, Danel C, Couzon F, Dumitrescu O, Lilin T, Perronne C, Etienne J, Lina G, and Vandenesch F
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- Abscess microbiology, Animals, Antibodies, Bacterial blood, Bacterial Toxins genetics, Exotoxins genetics, Female, Gene Expression Regulation, Bacterial physiology, Hemolysin Proteins genetics, Immunoglobulin G blood, Leukocidins genetics, Lung Diseases microbiology, Lung Diseases pathology, Methicillin-Resistant Staphylococcus aureus genetics, Mutation, Osteomyelitis mortality, Osteomyelitis pathology, Rabbits, Sepsis complications, Staphylococcal Infections mortality, Bacterial Toxins metabolism, Exotoxins metabolism, Hemolysin Proteins metabolism, Leukocidins metabolism, Methicillin-Resistant Staphylococcus aureus metabolism, Osteomyelitis microbiology, Sepsis microbiology, Staphylococcal Infections microbiology
- Abstract
Background: Severe sepsis, combining acute osteomyelitis and lung involvement, has been described increasingly in healthy children with the spread of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)., Methods: Outcomes (mortality, hematogenous spread, lung and bone involvements) of rabbit osteomyelitis caused by CA-MRSA LAC(WT) USA300 and its Panton-Valentine leukocidin (PVL)- and α-hemolysin (Hla)-negative isogenic derivatives (LACΔpvl and LACΔhla, respectively) were compared., Results: Three days after inoculation (D3), all LAC(WT)- and LACΔpvl-, and 72% of LACΔhla-infected rabbits had no hematogenous spread and similar lung and bone bacterial densities. LACΔpvl and LACΔhla caused less severe histological lung lesions than LAC(WT) (P ≤ .01). Between D3 and D9, 10 (53%) LAC(WT)-, 11 (55%) LACΔpvl-, but no LACΔhla-infected rabbits (P < .005) died of severe sepsis with disseminated infection. Unlike deceased animals, most LAC(WT), LACΔpvl, and LACΔhla D14 survivors had no hematogenous spread (P < .001). LAC(WT) (88%) caused more bone abscesses than LACΔpvl (0, P = .001) or LACΔhla (30%, P = .01)., Conclusion: In this model, both PVL and Hla seemed to be required for early lung involvement via hematogenous spread. Hla, but not PVL, significantly impacted severe sepsis-related mortality. PVL was the predominant factor determining late-stage bone abscesses.
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- 2014
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14. PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts.
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Rasigade JP, Trouillet-Assant S, Ferry T, Diep BA, Sapin A, Lhoste Y, Ranfaing J, Badiou C, Benito Y, Bes M, Couzon F, Tigaud S, Lina G, Etienne J, Vandenesch F, and Laurent F
- Subjects
- Bacterial Load, Cell Death drug effects, Community-Acquired Infections microbiology, Delivery of Health Care, Gene Expression Regulation, Bacterial, Humans, Osteoblasts drug effects, RNA, Messenger genetics, RNA, Messenger metabolism, Species Specificity, Bacterial Toxins toxicity, Intracellular Space drug effects, Intracellular Space microbiology, Methicillin-Resistant Staphylococcus aureus physiology, Osteoblasts cytology, Osteoblasts microbiology
- Abstract
Epidemic community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is associated with more severe and acute forms of osteomyelitis than healthcare-associated (HA-) MRSA. Although S. aureus is now recognized as a facultative intracellular pathogen, the contribution of osteoblast invasion by CA-MRSA to the pathogenesis of osteomyelitis is unknown. Using an ex vivo model of intracellular infection of human osteoblasts, we demonstrated that CA-MRSA strains of diverse lineages share an enhanced ability to kill infected osteoblasts compared to HA-MRSA. Cytotoxicity comparisons of CA-MRSA isogenic deletion mutants revealed that phenol-soluble modulins (PSMs), a class of membrane-damaging exoproteins that are expressed at higher levels in CA-MRSA than in HA-MRSA, are involved in this osteoblast killing, whereas other major CA-MRSA virulence determinants, the Panton-Valentine leukocidin and alpha-toxin, are not involved. Similarly, functional agr and sarA regulators, which control the expression of PSMs and alpha-toxin, were required for the expression of the intracellular cytotoxic phenotype by CA-MRSA, whereas the saeRS regulator, which controls the expression of alpha-toxin but not PSMs, had no impact on cytotoxicity. Finally, PSM transcript levels determined by quantitative reverse-transcriptase PCR were significantly higher in CA-MRSA than in HA-MRSA strains and associated with cell damage in MRSA-infected osteoblasts. These findings provide new insights into the pathogenesis of severe CA-MRSA osteomyelitis and unravel a novel virulence strategy of CA-MRSA, based on the invasion and subsequent killing of osteoblasts by PSMs acting as intracellular toxins.
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- 2013
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15. Cross-talk between Staphylococcus aureus leukocidins-intoxicated macrophages and lung epithelial cells triggers chemokine secretion in an inflammasome-dependent manner.
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Perret M, Badiou C, Lina G, Burbaud S, Benito Y, Bes M, Cottin V, Couzon F, Juruj C, Dauwalder O, Goutagny N, Diep BA, Vandenesch F, and Henry T
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- Animals, Child, Humans, Lung immunology, Lung pathology, Macrophages immunology, Neutrophils immunology, Staphylococcus aureus immunology, Virulence Factors metabolism, Young Adult, Bacterial Toxins metabolism, Chemokines metabolism, Epithelial Cells immunology, Exotoxins metabolism, Inflammasomes metabolism, Interleukin-1beta metabolism, Leukocidins metabolism, Macrophages microbiology, Staphylococcus aureus pathogenicity
- Abstract
Staphylococcus aureus is a major pathogen responsible for both nosocomial and community-acquired infections. Central to its virulence is its ability to secrete haemolysins, pore-forming toxins and cytolytic peptides. The large number of membrane-damaging toxins and peptides produced during S. aureus infections has hindered a precise understanding of their specific roles in diseases. Here, we used comprehensive libraries of recombinant toxins and synthetic cytolytic peptides, of S. aureus mutants and clinical strains to investigate the role of these virulence factors in targeting human macrophages and triggering IL-1β release. We found that the Panton Valentine leukocidin (PVL) is the major trigger of IL-1β release and inflammasome activation in primary human macrophages. The cytolytic peptides, δ-haemolysin and PSMα3; the pore-forming toxins, γ-haemolysin and LukDE; and β-haemolysin synergize with PVL to amplify IL-1β release, indicating that these factors cooperate with PVL to trigger inflammation. PVL(+) S. aureus causes necrotizing pneumonia in children and young adults. The severity of this disease is due to the massive recruitment of neutrophils that cause lung damage. Importantly, we demonstrate that PVL triggers IL-1β release in human alveolar macrophages. Furthermore, IL-1β released by PVL-intoxicated macrophages stimulates the secretion of the neutrophil attracting chemokines, IL-8 and monocyte chemotactic protein-1, by lung epithelial cells. Finally, we show that PVL-induced IL-8/monocyte chemotactic protein-1 release is abolished by the inclusion of IL-1 receptor antagonist (IL-1Ra) in a mixed culture of lung epithelial cells and macrophages. Together, our results identify PVL as the predominant S. aureus secreted factor for triggering inflammasome activation in human macrophages and demonstrate how PVL-intoxicated macrophages orchestrate inflammation in the lung. Finally, our work suggests that anakinra, a synthetic IL-1Ra, may be an effective therapeutic agent to reduce the massive neutrophils infiltration observed during necrotizing pneumonia and decrease the resulting host-mediated lung injury., (© 2012 Blackwell Publishing Ltd.)
- Published
- 2012
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16. The Panton-Valentine leukocidin is a virulence factor in a murine model of necrotizing pneumonia.
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Vandenesch F, Couzon F, Boisset S, Benito Y, Brown EL, Lina G, Etienne J, and Bowden MG
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- Animals, Bacterial Proteins metabolism, Bacterial Toxins, Enzyme-Linked Immunosorbent Assay, Humans, Mice, Point Mutation, Staphylococcus aureus genetics, Trans-Activators metabolism, Virulence, Bacterial Proteins genetics, Exotoxins physiology, Leukocidins physiology, Pneumonia, Staphylococcal microbiology, Staphylococcus aureus pathogenicity, Trans-Activators genetics, Virulence Factors physiology
- Published
- 2010
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17. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia.
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Labandeira-Rey M, Couzon F, Boisset S, Brown EL, Bes M, Benito Y, Barbu EM, Vazquez V, Höök M, Etienne J, Vandenesch F, and Bowden MG
- Subjects
- Animals, Bacterial Proteins genetics, Bacterial Proteins metabolism, Bacterial Toxins genetics, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Disease Models, Animal, Exotoxins genetics, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Hemorrhage, Leukocidins genetics, Lung microbiology, Methicillin Resistance, Mice, Mice, Inbred BALB C, Necrosis, Oligonucleotide Array Sequence Analysis, Staphylococcal Protein A genetics, Staphylococcus aureus genetics, Staphylococcus aureus growth & development, Staphylococcus aureus metabolism, Transcription, Genetic, Virulence, Virulence Factors genetics, Exotoxins physiology, Leukocidins physiology, Lung pathology, Pneumonia, Staphylococcal microbiology, Pneumonia, Staphylococcal pathology, Staphylococcal Protein A metabolism, Staphylococcus aureus pathogenicity, Virulence Factors physiology
- Abstract
The Staphylococcus aureus Panton-Valentine leukocidin (PVL) is a pore-forming toxin secreted by strains epidemiologically associated with the current outbreak of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and with the often-lethal necrotizing pneumonia. To investigate the role of PVL in pulmonary disease, we tested the pathogenicity of clinical isolates, isogenic PVL-negative and PVL-positive S. aureus strains, as well as purified PVL, in a mouse acute pneumonia model. Here we show that PVL is sufficient to cause pneumonia and that the expression of this leukotoxin induces global changes in transcriptional levels of genes encoding secreted and cell wall-anchored staphylococcal proteins, including the lung inflammatory factor staphylococcal protein A (Spa).
- Published
- 2007
- Full Text
- View/download PDF
18. Alterations of anaphase-promoting complex genes in human colon cancer cells.
- Author
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Wang Q, Moyret-Lalle C, Couzon F, Surbiguet-Clippe C, Saurin JC, Lorca T, Navarro C, and Puisieux A
- Subjects
- Anaphase-Promoting Complex-Cyclosome, Antineoplastic Agents pharmacology, Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome, Apc6 Subunit, Anaphase-Promoting Complex-Cyclosome, Apc8 Subunit, Anaphase-Promoting Complex-Cyclosome, Breast Neoplasms genetics, Carcinoma, Hepatocellular genetics, Cell Cycle genetics, Cell Cycle Proteins drug effects, Cell Cycle Proteins genetics, Colonic Neoplasms drug therapy, Cyclin B genetics, Cyclin B metabolism, Cyclin B1, Epithelial Cells pathology, Epithelial Cells physiology, Female, Humans, Ligases metabolism, Liver Neoplasms genetics, Melanoma genetics, Mitosis, Mutation, Neuroblastoma genetics, Nocodazole pharmacology, Ovarian Neoplasms genetics, Polymerase Chain Reaction methods, Protein Subunits, Tumor Cells, Cultured, Colonic Neoplasms genetics, Ligases genetics, Ubiquitin-Protein Ligase Complexes
- Abstract
Ubiquitin-mediated proteolysis of cell cycle regulators is a major element of the cell cycle control. The anaphase-promoting complex (APC/C) is a large multisubunit ubiquitin-protein ligase required for the ubiquitination and degradation of G1 and mitotic checkpoint regulators. APC/C-dependent proteolysis regulates cyclin levels in G1, and triggers the separation of sister chromatids at the metaphase-anaphase transition and the destruction of mitotic cyclins at the end of mitosis. Furthermore, it was recently shown that APC/C regulates the degradation of crucial regulators of signal transduction pathways. We report here gene alterations in several components of this complex in human colon cancer cells, including APC6/CDC16 and APC8/CDC23 which are known to be key function elements. The experimental expression of a truncation mutant of APC8/CDC23 subunit (CDC23DeltaTPR) leads to abnormal levels of APC/C targets such as cyclin B1 and disturbs the cell cycle progression of colon epithelial cells through mitosis. Overall, these data support the hypothesis of a deleterious role of these mutations during colorectal carcinogenesis.
- Published
- 2003
- Full Text
- View/download PDF
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