Neutrophil Extracellular Traps Enhance Staphylococcus Aureus Vegetation Formation through Interaction with Platelets in Infective Endocarditis

2019 ◽  
Vol 119 (05) ◽  
pp. 786-796 ◽  
Author(s):  
Chih-Chieh Hsu ◽  
Ron-Bin Hsu ◽  
Ryosuke Ohniwa ◽  
Jeng-Wei Chen ◽  
Chang-Tsu Yuan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Infective Endocarditis ◽  
Synergistic Effects ◽  
Neutrophil Extracellular Traps ◽  
Dnase I ◽  
Extracellular Traps ◽  
Vitro Data ◽  
In Vitro Data ◽  
Vegetation Formation

AbstractThe mechanisms or host factors involved in septic thrombus or vegetation formation in Staphylococcus aureus-induced infective endocarditis (IE) are unclear. Using an experimental endocarditis rat model, here we demonstrated that S. aureus HG001-induced vegetation was composed of bacterial floes encased in aggregated platelets and surrounded by neutrophil extracellular traps (NETs). In vitro data demonstrated that platelets contribute to both biofilm and NET formation. Prophylactic administration of DNase I significantly reduced the size of vegetation induced by methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) strains, even though MRSA and MSSA isolates express different biofilm phenotypes and NET-induction abilities in the presence of platelets. Moreover, delivery of both DNase I and daptomycin prophylactically and therapeutically produced synergistic effects by reducing vegetation size and bacterial numbers on damaged valve tissues in MRSA-induced IE. Together, these data suggest that NETs contribute to vegetation formation in S. aureus endocarditis and DNase I has the potential to control S. aureus-induced IE in the clinic.

scholarly journals The Involvement of Neutrophil Extracellular Traps in Disease Activity Associated With IgA Vasculitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiu-Qi Chen ◽  
Li Tu ◽  
Jia-Sen Zou ◽  
Shi-Qun Zhu ◽  
Yan-Jun Zhao ◽  
...  
Keyword(s):  
Disease Activity ◽  
Drug Withdrawal ◽  
Neutrophil Extracellular Traps ◽  
Dnase I ◽  
Healthy Children ◽  
Healthy Controls ◽  
Iga Vasculitis ◽  
Extracellular Traps ◽  
Circulating Levels

ObjectivesThis aim of this study was to determine whether neutrophil extracellular traps (NETs) are involved in the pathogenesis of IgA vasculitis (IgAV) and investigate whether the circulating NETs levels are associated with disease activity in children.MethodsWe performed a case-control study and collected blood samples from 193 children with different stages of IgAV (61 were at the onset stage, 64 at the remission stage, 43 at the active stage, and 25 were undergoing drug withdrawal). A total of 192 healthy children were recruited as controls. Circulating cell free DNA (cf-DNA) was obtained from the plasma and quantified by using the Quant-iT PicoGreen DNA quantification kit. NETs-associated myeloperoxidase-DNA (MPO-DNA), citrullinated-histone H3 (cit-H3), neutrophil elastase (NE), and the deoxyribonuclease I (DNase I) concentrations were measured using enzyme-linked immunosorbent assays. The presence of NETs in the kidney and gastrointestinal tissues of onset and active IgAV patients was determined by multiple immunofluorescence staining in 15 IgAV nephritis patients and 9 IgAV patients without IgAV nephritis, respectively. NETs degradation potency of collected sera samples from IgAV patients were checked in vitro. Relationships between circulating levels of cf-DNA with MPO-DNA, NE, and DNase I and the patients were analyzed.ResultsCirculating levels of cf-DNA in onset and active IgAV patients were significantly higher than those in remission and drug withdrawal patients as well as healthy controls. The results were similar for MPO-DNA and NE. The levels of circulating cf-DNA correlated significantly with MPO-DNA, NE and DNase I. A significantly decreased degradation of NETs from the onset and active IgAV patients was observed, but was normal in healthy controls. Furthermore, presence of NETs was also confirmed in all renal and gastrointestinal tissues obtained from the onset and active IgAV patients but not control samples.ConclusionsOur data showed that NETs were released into the circulation of IgAV patients and are involved in the disease activity. The circulating levels of NETs maybe used to assess disease severity in children with IgAV.

scholarly journals α-Synuclein modulates tau spreading in mouse brains

2020 ◽  
Vol 218 (1) ◽  
Author(s):  
Fares Bassil ◽  
Emily S. Meymand ◽  
Hannah J. Brown ◽  
Hong Xu ◽  
Timothy O. Cox ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Synergistic Effects ◽  
Tau Pathology ◽  
Vitro Data ◽  
In Vitro Data

α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson’s disease (PD) and Alzheimer’s disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological α-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of α-syn mousepreformed fibrils (mpffs) and AD lysate–derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse α-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of α-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on α-syn. Our results point to the important role of α-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.

scholarly journals Thermonucleases Contribute to Staphylococcus aureus Biofilm Formation in Implant-Associated Infections–A Redundant and Complementary Story

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinlong Yu ◽  
Feng Jiang ◽  
Feiyang Zhang ◽  
Musha Hamushan ◽  
Jiafei Du ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mouse Model ◽  
Immune Evasion ◽  
Biofilm Formation ◽  
Bacterial Load ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps ◽  
Bacterial Aggregation ◽  
Scanning Electron

Biofilms formed by Staphylococcus aureus are one of the predominant causes of implant-associated infections (IAIs). Previous studies have found that S. aureus nucleases nuc1 and nuc2 modulate biofilm formation. In this study, we found low nuc1/nuc2 expression and high biofilm-forming ability among IAI isolates. Furthermore, in a mouse model of exogenous IAIs, Δnuc1/2 exhibited higher bacterial load on the surface of the implant than that exhibited by the other groups (WT, Δnuc1, and Δnuc2). Survival analysis of the hematogenous IAI mouse model indicated that nuc1 is a virulence factor related to mortality. We then detected the influence of nuc1 and nuc2 on biofilm formation and immune evasion in vitro. Observation of in vitro biofilm structures with scanning electron microscopy and evaluation of bacterial aggregation with flow cytometry revealed that both nuc1 and nuc2 are involved in biofilm structuring and bacterial aggregation. Unlike nuc1, which is reported to participate in immune evasion, nuc2 cannot degrade neutrophil extracellular traps. Moreover, we found that nuc1/nuc2 transcription is negatively correlated during S. aureus growth, and a possible complementary relationship has been proposed. In conclusion, nuc1/nuc2 are complementary genes involved in biofilm formation in exogenous IAIs. However, nuc2 contributes less to virulence and is not involved in immune evasion.

scholarly journals Ceftaroline in the treatment of methicillin-resistant and daptomycin-non-susceptible Staphylococcus aureus bacteremia and infective endocarditis in end-stage renal disease

2013 ◽  
Vol 1 (4) ◽  
pp. 53
Author(s):  
Kristen Fuhrmann ◽  
Richard Winn ◽  
Paula McKenzie ◽  
Mamoun Bashir
Keyword(s):  
Staphylococcus Aureus ◽  
Case Reports ◽  
Kinetic Properties ◽  
Methicillin Resistant ◽  
Staphylococcus Aureus Bacteremia ◽  
Stage Renal Disease ◽  
End Stage ◽  
Vitro Data ◽  
In Vitro Data

As bacteria evolve and become resistant to preferred antibiotics, we often have toresort to alternative, second-line agents for treatment. This case highlights a growingtrend being observed among methicillin-resistant Staphylococcus aureus (MRSA)isolates, in which the minimum inhibitory concentration breakpoints start to increaseand traditional therapy fails. When clinicians are faced with a difficult to treat infectionand constrained by declining renal function, drug allergies, or clinical scenario, it maybe prudent to use therapy that is supported by only in vitro data, animal models, andstrong case reports. Combining knowledge of the drug’s kinetic properties, mechanismof action, safety, and adverse effect profile, and literature to support its use helpedguide our decision in treating a patient with persistent MRSA bacteremia and infectiveendocarditis.

scholarly journals Synergistic Activity of Ceftobiprole and Vancomycin in a Rat Model of Infective Endocarditis Caused by Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus

2012 ◽  
Vol 56 (3) ◽  
pp. 1476-1484 ◽  
Author(s):  
Jeffrey Fernandez ◽  
Darren Abbanat ◽  
Wenchi Shang ◽  
Wenping He ◽  
Karen Amsler ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Infective Endocarditis ◽  
Rat Model ◽  
Synergistic Effects ◽  
Synergistic Activity ◽  
Methicillin Resistant ◽  
Content Type ◽  
Cell Densities

ABSTRACTThe therapeutic activity of ceftobiprole medocaril, the prodrug of ceftobiprole, was compared to that of vancomycin, daptomycin, and the combination of a subtherapeutic dose of ceftobiprole and vancomycin in a rat model of infective endocarditis due to methicillin-resistantStaphylococcus aureus(MRSA) (ATCC 43300) or glycopeptide-intermediateStaphylococcus aureus(GISA) (NRS4 and HIP 5836) strains. The minimum bactericidal concentrations of ceftobiprole, vancomycin, and daptomycin at bacterial cell densities similar to those encountered in the cardiac vegetation in the rat endocarditis model were 2, >64, and 8 μg/ml, respectively, for MRSA ATCC 43300 and 4, >64, and 8 μg/ml, respectively, for the GISA strain. Ceftobiprole medocaril administered in doses of 100 mg/kg of body weight given intravenously (i.v.) twice a day (BID) every 8 h (q8h) (equivalent to a human therapeutic dose of ceftobiprole [500 mg given three times a day [TID]) was the most effective monotherapy, eradicating nearly 5 log10CFU/g MRSA or 6 log10CFU/g GISA organisms from the cardiac vegetation and had the highest incidence of sterile vegetation compared to the other monotherapies in the endocarditis model. Inin vitrotime-kill studies, synergistic effects were observed with ceftobiprole and vancomycin on MRSA and GISA strains, andin vivosynergy was noted with combinations of subtherapeutic doses of these agents for the same strains. Additionally, sterile vegetations were achieved in 33 and 60%, respectively, of the animals infected with MRSA ATCC 43300 or GISA NRS4 receiving ceftobiprole-vancomycin combination therapy. In summary, ceftobiprole was efficacious both as monotherapy and in combination with vancomycin in treating MRSA and GISA infections in a rat infective endocarditis model and warrants further evaluation.

scholarly journals Synergistic antibacterial combination of Lavandula latifolia Medik. essential oil with camphor

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Nursenem Karaca ◽  
Görkem Şener ◽  
Betül Demirci ◽  
Fatih Demirci
Keyword(s):  
Staphylococcus Aureus ◽  
Essential Oil ◽  
Antibacterial Effect ◽  
Synergistic Effects ◽  
Pharmaceutical Formulations ◽  
Human Pathogens ◽  
Broth Microdilution ◽  
Antibacterial Effects ◽  
Lavandula Latifolia

AbstractCombination of various compounds and essential oils for pharmaceutical formulations withdraw attention. In this present study, it was aimed to evaluate the in vitro potential synergistic antibacterial effect of Lavandula latifolia (spike lavender) essential oil with camphor by using the checkerboard method against the human pathogens; Staphylococcus aureus and Listeria monocytogenes. Pharmacopoeia quality L. latifolia essential oil and racemic camphor were analyzed and verified by GC-FID and GC/MS, simultaneously. In vitro antibacterial activity of essential oil and camphor (MIC range: 0.16–20 mg/mL) and standard antimicrobial clarithromycin (MIC range: 0.125–16 μg/mL) were carried out by broth microdilution against S. aureus and L. monocytogenes standard strains, respectively. Resulting antibacterial effects were evaluated for their fractional inhibitory concentrations (FICs) as antagonistic, additive and synergistic effects. The analytical results showed that the major component of essential oil was linalool (45.2%) and 1,8-cineole (25.6%). Antibacterial effects of essential oil were determined as MIC 1.25–5 mg/mL. As a result of the experiments, L. latifolia essential oil–camphor combinations were identified as “synergistic (FIC ≤ 0.5), and additive (0.5 < FIC ≤ 1)” in the respective combinations, suggesting further evaluation for formulations for potential antimicrobial applications in food and pharmaceuticals.

Use of Toxicokinetics in Risk Assessment Based on In Vitro Data

1993 ◽  
Vol 21 (2) ◽  
pp. 173-180
Author(s):  
Gunnar Johanson
Keyword(s):  
Risk Assessment ◽  
Whole Body ◽  
External Exposure ◽  
Target Dose ◽  
Toxic Response ◽  
Route Of Exposure ◽  
Vitro Data ◽  
In Vitro Data

This presentation addresses some aspects of the methodology, advantages and problems associated with toxicokinetic modelling based on in vitro data. By using toxicokinetic models, particularly physiologically-based ones, it is possible, in principle, to describe whole body toxicokinetics, target doses and toxic effects from in vitro data. Modelling can be divided into three major steps: 1) to relate external exposure (applied dose) of xenobiotic to target dose; 2) to establish the relationship between target dose and effect (in vitro data, e.g. metabolism in microsomes, partitioning in tissue homogenates, and toxicity in cell cultures, are useful in both steps); and 3) to relate external exposure to toxic effect by combining the first two steps. Extrapolations from in vitro to in vivo, between animal and man, and between high and low doses, can easily be carried out by toxicokinetic simulations. In addition, several factors that may affect the toxic response by changing the target dose, such as route of exposure and physical activity, can be studied. New insights concerning the processes involved in toxicity often emerge during the design, refinement and validation of the model. The modelling approach is illustrated by two examples: 1) the carcinogenicity of 1,3-butadiene; and 2) the haematotoxicity of 2-butoxyethanol. Toxicokinetic modelling is an important tool in toxicological risk assessment based on in vitro data. Many factors, some of which can, and should be, studied in vitro, are involved in the expression of toxicity. Successful modelling depends on the identification and quantification of these factors.

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