DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase
BackgroundStaphylocoagulase (SCG) is a virulence factor of Staphylococcus aureus, one of the most lethal pathogens of our times. The complex of SCG with prothrombin (SCG/ProT) can clot fibrinogen, and SCG/ProT-induced fibrin and plasma clots have been described to show decreased mechanical and lytic...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-08-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1233128/full |
| _version_ | 1797741413423644672 |
|---|---|
| author | Erzsébet Komorowicz Veronika J. Farkas László Szabó László Szabó Sophie Cherrington Craig Thelwell Krasimir Kolev |
| author_facet | Erzsébet Komorowicz Veronika J. Farkas László Szabó László Szabó Sophie Cherrington Craig Thelwell Krasimir Kolev |
| author_sort | Erzsébet Komorowicz |
| collection | DOAJ |
| description | BackgroundStaphylocoagulase (SCG) is a virulence factor of Staphylococcus aureus, one of the most lethal pathogens of our times. The complex of SCG with prothrombin (SCG/ProT) can clot fibrinogen, and SCG/ProT-induced fibrin and plasma clots have been described to show decreased mechanical and lytic resistance, which may contribute to septic emboli from infected cardiac vegetations. At infection sites, neutrophils can release DNA and histones, as parts of neutrophil extracellular traps (NETs), which in turn favor thrombosis, inhibit fibrinolysis and strengthen clot structure.ObjectivesTo characterize the combined effects of major NET-components (DNA, histone H1 and H3) on SCG/ProT-induced clot structure, mechanical and lytic stability.MethodsRecombinant SCG was used to clot purified fibrinogen and plasma. The kinetics of formation and lysis of fibrin and plasma clots containing H1 or core histones+/-DNA were followed by turbidimetry. Fibrin structure and mechanical stability were characterized with scanning electron microscopy, pressure-driven permeation, and oscillation rheometry.ResultsHistones and DNA favored the formation of thicker fibrin fibers and a more heterogeneous clot structure including high porosity with H1 histone, whereas low porosity with core histones and DNA. As opposed to previous observations with thrombin-induced clots, SCG/ProT-induced fibrin was not mechanically stabilized by histones. Similarly to thrombin-induced clots, the DNA-histone complexes prolonged fibrinolysis with tissue-type plasminogen activator (up to 2-fold). The anti-fibrinolytic effect of the DNA and DNA-H3 complex was observed in plasma clots too. Heparin (low molecular weight) accelerated the lysis of SCG/ProT-clots from plasma, even if DNA and histones were also present.ConclusionsIn the interplay of NETs and fibrin formed by SCG, DNA and histones promote structural heterogeneity in the clots, and fail to stabilize them against mechanical stress. The DNA-histone complexes render the SCG-fibrin more resistant to lysis and thereby less prone to embolization. |
| first_indexed | 2024-03-12T14:26:21Z |
| format | Article |
| id | doaj.art-7a06c32c347542659be46520071585ee |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T14:26:21Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-7a06c32c347542659be46520071585ee2023-08-18T07:06:11ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-08-011410.3389/fimmu.2023.12331281233128DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulaseErzsébet Komorowicz0Veronika J. Farkas1László Szabó2László Szabó3Sophie Cherrington4Craig Thelwell5Krasimir Kolev6Institute of Biochemistry and Molecular Biology, Department of Biochemistry, Semmelweis University, Budapest, HungaryInstitute of Biochemistry and Molecular Biology, Department of Biochemistry, Semmelweis University, Budapest, HungaryInstitute of Biochemistry and Molecular Biology, Department of Biochemistry, Semmelweis University, Budapest, HungaryPlasma Chemistry Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Budapest, HungarySouth Mimms Laboratories, Medicines and Healthcare Products Regulatory Agency, Potters Bar, United KingdomSouth Mimms Laboratories, Medicines and Healthcare Products Regulatory Agency, Potters Bar, United KingdomInstitute of Biochemistry and Molecular Biology, Department of Biochemistry, Semmelweis University, Budapest, HungaryBackgroundStaphylocoagulase (SCG) is a virulence factor of Staphylococcus aureus, one of the most lethal pathogens of our times. The complex of SCG with prothrombin (SCG/ProT) can clot fibrinogen, and SCG/ProT-induced fibrin and plasma clots have been described to show decreased mechanical and lytic resistance, which may contribute to septic emboli from infected cardiac vegetations. At infection sites, neutrophils can release DNA and histones, as parts of neutrophil extracellular traps (NETs), which in turn favor thrombosis, inhibit fibrinolysis and strengthen clot structure.ObjectivesTo characterize the combined effects of major NET-components (DNA, histone H1 and H3) on SCG/ProT-induced clot structure, mechanical and lytic stability.MethodsRecombinant SCG was used to clot purified fibrinogen and plasma. The kinetics of formation and lysis of fibrin and plasma clots containing H1 or core histones+/-DNA were followed by turbidimetry. Fibrin structure and mechanical stability were characterized with scanning electron microscopy, pressure-driven permeation, and oscillation rheometry.ResultsHistones and DNA favored the formation of thicker fibrin fibers and a more heterogeneous clot structure including high porosity with H1 histone, whereas low porosity with core histones and DNA. As opposed to previous observations with thrombin-induced clots, SCG/ProT-induced fibrin was not mechanically stabilized by histones. Similarly to thrombin-induced clots, the DNA-histone complexes prolonged fibrinolysis with tissue-type plasminogen activator (up to 2-fold). The anti-fibrinolytic effect of the DNA and DNA-H3 complex was observed in plasma clots too. Heparin (low molecular weight) accelerated the lysis of SCG/ProT-clots from plasma, even if DNA and histones were also present.ConclusionsIn the interplay of NETs and fibrin formed by SCG, DNA and histones promote structural heterogeneity in the clots, and fail to stabilize them against mechanical stress. The DNA-histone complexes render the SCG-fibrin more resistant to lysis and thereby less prone to embolization.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1233128/fullstaphylocoagulasefibrinfibrinolysisNEThistoneextracellular DNA |
| spellingShingle | Erzsébet Komorowicz Veronika J. Farkas László Szabó László Szabó Sophie Cherrington Craig Thelwell Krasimir Kolev DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase Frontiers in Immunology staphylocoagulase fibrin fibrinolysis NET histone extracellular DNA |
| title | DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase |
| title_full | DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase |
| title_fullStr | DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase |
| title_full_unstemmed | DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase |
| title_short | DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase |
| title_sort | dna and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase |
| topic | staphylocoagulase fibrin fibrinolysis NET histone extracellular DNA |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1233128/full |
| work_keys_str_mv | AT erzsebetkomorowicz dnaandhistonesimpairthemechanicalstabilityandlyticsusceptibilityoffibrinformedbystaphylocoagulase AT veronikajfarkas dnaandhistonesimpairthemechanicalstabilityandlyticsusceptibilityoffibrinformedbystaphylocoagulase AT laszloszabo dnaandhistonesimpairthemechanicalstabilityandlyticsusceptibilityoffibrinformedbystaphylocoagulase AT laszloszabo dnaandhistonesimpairthemechanicalstabilityandlyticsusceptibilityoffibrinformedbystaphylocoagulase AT sophiecherrington dnaandhistonesimpairthemechanicalstabilityandlyticsusceptibilityoffibrinformedbystaphylocoagulase AT craigthelwell dnaandhistonesimpairthemechanicalstabilityandlyticsusceptibilityoffibrinformedbystaphylocoagulase AT krasimirkolev dnaandhistonesimpairthemechanicalstabilityandlyticsusceptibilityoffibrinformedbystaphylocoagulase |