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Gayathri Arakere - One of the best experts on this subject based on the ideXlab platform.
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Modelling Staphylococcal Pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
Disease Models & Mechanisms, 2015Co-Authors: Srikanth Mairpady Shambat, François Vandenesch, Gérard Lina, Puran Chen, Anh Thu Nguyen Hoang, Helena Bergsten, Nikolai Siemens, Ian R. Monk, Timothy J. Foster, Gayathri ArakereAbstract:Staphylococcus aureus necrotizing Pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific Staphylococcal exotoxins in tissue pathology associated with severe Pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing Pneumonia or lung empyema, or to purified toxins. The necrotizing Pneumonia strains secreted high levels of α-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of α-toxin, and triggered limited tissue damage. α-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure α-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of α-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with Staphylococcal Pneumonia revealed that strains producing high levels of α-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against α-toxin and PVL. This study introduces a novel model system for study of Staphylococcal Pneumonia in a human setting. The results reveal that the combination and levels of α-toxin and PVL correlate with tissue pathology and clinical outcome associated with Pneumonia.
Srikanth Mairpady Shambat - One of the best experts on this subject based on the ideXlab platform.
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Modelling Staphylococcal Pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
Disease Models & Mechanisms, 2015Co-Authors: Srikanth Mairpady Shambat, François Vandenesch, Gérard Lina, Puran Chen, Anh Thu Nguyen Hoang, Helena Bergsten, Nikolai Siemens, Ian R. Monk, Timothy J. Foster, Gayathri ArakereAbstract:Staphylococcus aureus necrotizing Pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific Staphylococcal exotoxins in tissue pathology associated with severe Pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing Pneumonia or lung empyema, or to purified toxins. The necrotizing Pneumonia strains secreted high levels of α-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of α-toxin, and triggered limited tissue damage. α-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure α-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of α-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with Staphylococcal Pneumonia revealed that strains producing high levels of α-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against α-toxin and PVL. This study introduces a novel model system for study of Staphylococcal Pneumonia in a human setting. The results reveal that the combination and levels of α-toxin and PVL correlate with tissue pathology and clinical outcome associated with Pneumonia.
Gérard Lina - One of the best experts on this subject based on the ideXlab platform.
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In vitro activity of ceftobiprole on 440 Staphylococcus aureus strains isolated from bronchopulmonary infections
Médecine et Maladies Infectieuses, 2017Co-Authors: Elisabeth Hodille, L. Delouere, C. Bouveyron, Hélène Meugnier, Michèle Bes, Anne Tristan, Frédéric Laurent, François Vandenesch, Gérard Lina, Oana DumitrescuAbstract:OBJECTIVE: We assessed the in vitro activity of ceftobiprole on 440 Staphylococcus aureus clinical strains isolated from bronchopulmonary infections (2010-2014). METHODS: S.~aureus isolates were characterized for methicillin resistance, PVL status, and clonal complex. All isolates were tested for minimal inhibitory concentrations (MIC) determination by broth microdilution method for ceftobiprole, ceftaroline fosamil, and comparator antibiotics (linezolid, tigecycline, vancomycin, and daptomycin). RESULTS: A total of 325 (74%) strains were methicillin-susceptible S.~aureus (MSSA) and 115 (26%) were methicillin-resistant S.~aureus (MRSA); 105 (24%) S.~aureus strains were PVL-positive, including 35.2% (37/105) MRSA and 64.8% (68/105) MSSA. Ceftobiprole was highly active against S.~aureus with MIC90 of 1~mg/L, MICs ranging between 0.12 and 4mg/L (only one resistant strain, MIC of 4~mg/L). MIC50 and MIC90 were twice lower in MSSA than MRSA. Moreover, PVL+ MRSA were slightly more susceptible to ceftobiprole (MIC50 of 0.5~mg/L and MIC90 of 1~mg/L) than PVL- MRSA (MIC50 and MIC90 of 1~mg/L). The ceftobiprole-resistant strain was also resistant to ceftaroline fosamil and presented the D239L mutation in PBP2A. The comparator antibiotics were equally active on the strains tested, with MIC90 of 0.5~mg/L for ceftaroline fosamil, tigecycline, and daptomycin; 1~mg/L for vancomycin; and 2~mg/L for linezolid. CONCLUSIONS: Our results suggest that ceftobiprole is highly active against S.~aureus and is an effective alternative to vancomycin or linezolid in the management of Staphylococcal Pneumonia. However, close monitoring of isolates should be maintained to prevent resistant strain diffusion.
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Modelling Staphylococcal Pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
Disease Models & Mechanisms, 2015Co-Authors: Srikanth Mairpady Shambat, François Vandenesch, Gérard Lina, Puran Chen, Anh Thu Nguyen Hoang, Helena Bergsten, Nikolai Siemens, Ian R. Monk, Timothy J. Foster, Gayathri ArakereAbstract:Staphylococcus aureus necrotizing Pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific Staphylococcal exotoxins in tissue pathology associated with severe Pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing Pneumonia or lung empyema, or to purified toxins. The necrotizing Pneumonia strains secreted high levels of α-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of α-toxin, and triggered limited tissue damage. α-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure α-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of α-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with Staphylococcal Pneumonia revealed that strains producing high levels of α-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against α-toxin and PVL. This study introduces a novel model system for study of Staphylococcal Pneumonia in a human setting. The results reveal that the combination and levels of α-toxin and PVL correlate with tissue pathology and clinical outcome associated with Pneumonia.
François Vandenesch - One of the best experts on this subject based on the ideXlab platform.
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In vitro activity of ceftobiprole on 440 Staphylococcus aureus strains isolated from bronchopulmonary infections
Médecine et Maladies Infectieuses, 2017Co-Authors: Elisabeth Hodille, L. Delouere, C. Bouveyron, Hélène Meugnier, Michèle Bes, Anne Tristan, Frédéric Laurent, François Vandenesch, Gérard Lina, Oana DumitrescuAbstract:OBJECTIVE: We assessed the in vitro activity of ceftobiprole on 440 Staphylococcus aureus clinical strains isolated from bronchopulmonary infections (2010-2014). METHODS: S.~aureus isolates were characterized for methicillin resistance, PVL status, and clonal complex. All isolates were tested for minimal inhibitory concentrations (MIC) determination by broth microdilution method for ceftobiprole, ceftaroline fosamil, and comparator antibiotics (linezolid, tigecycline, vancomycin, and daptomycin). RESULTS: A total of 325 (74%) strains were methicillin-susceptible S.~aureus (MSSA) and 115 (26%) were methicillin-resistant S.~aureus (MRSA); 105 (24%) S.~aureus strains were PVL-positive, including 35.2% (37/105) MRSA and 64.8% (68/105) MSSA. Ceftobiprole was highly active against S.~aureus with MIC90 of 1~mg/L, MICs ranging between 0.12 and 4mg/L (only one resistant strain, MIC of 4~mg/L). MIC50 and MIC90 were twice lower in MSSA than MRSA. Moreover, PVL+ MRSA were slightly more susceptible to ceftobiprole (MIC50 of 0.5~mg/L and MIC90 of 1~mg/L) than PVL- MRSA (MIC50 and MIC90 of 1~mg/L). The ceftobiprole-resistant strain was also resistant to ceftaroline fosamil and presented the D239L mutation in PBP2A. The comparator antibiotics were equally active on the strains tested, with MIC90 of 0.5~mg/L for ceftaroline fosamil, tigecycline, and daptomycin; 1~mg/L for vancomycin; and 2~mg/L for linezolid. CONCLUSIONS: Our results suggest that ceftobiprole is highly active against S.~aureus and is an effective alternative to vancomycin or linezolid in the management of Staphylococcal Pneumonia. However, close monitoring of isolates should be maintained to prevent resistant strain diffusion.
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Modelling Staphylococcal Pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
Disease Models & Mechanisms, 2015Co-Authors: Srikanth Mairpady Shambat, François Vandenesch, Gérard Lina, Puran Chen, Anh Thu Nguyen Hoang, Helena Bergsten, Nikolai Siemens, Ian R. Monk, Timothy J. Foster, Gayathri ArakereAbstract:Staphylococcus aureus necrotizing Pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific Staphylococcal exotoxins in tissue pathology associated with severe Pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing Pneumonia or lung empyema, or to purified toxins. The necrotizing Pneumonia strains secreted high levels of α-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of α-toxin, and triggered limited tissue damage. α-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure α-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of α-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with Staphylococcal Pneumonia revealed that strains producing high levels of α-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against α-toxin and PVL. This study introduces a novel model system for study of Staphylococcal Pneumonia in a human setting. The results reveal that the combination and levels of α-toxin and PVL correlate with tissue pathology and clinical outcome associated with Pneumonia.
Timothy J. Foster - One of the best experts on this subject based on the ideXlab platform.
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Modelling Staphylococcal Pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology
Disease Models & Mechanisms, 2015Co-Authors: Srikanth Mairpady Shambat, François Vandenesch, Gérard Lina, Puran Chen, Anh Thu Nguyen Hoang, Helena Bergsten, Nikolai Siemens, Ian R. Monk, Timothy J. Foster, Gayathri ArakereAbstract:Staphylococcus aureus necrotizing Pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific Staphylococcal exotoxins in tissue pathology associated with severe Pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing Pneumonia or lung empyema, or to purified toxins. The necrotizing Pneumonia strains secreted high levels of α-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of α-toxin, and triggered limited tissue damage. α-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure α-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of α-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with Staphylococcal Pneumonia revealed that strains producing high levels of α-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against α-toxin and PVL. This study introduces a novel model system for study of Staphylococcal Pneumonia in a human setting. The results reveal that the combination and levels of α-toxin and PVL correlate with tissue pathology and clinical outcome associated with Pneumonia.