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1.
  • Ali, Abukar, 1988, et al. (author)
  • Antibiotic-killed Staphylococcus aureus induces destructive arthritis in mice.
  • 2015
  • In: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 67:1, s. 107-116
  • Journal article (peer-reviewed)abstract
    • Objective: Permanent reduction in joint function is a severe post-infectious complication in patients with Staphylococcus aureus septic arthritis. This reduction in joint function might be caused by persistent joint inflammation after the adequate eradication of bacteria by antibiotics. Methods: We studied whether antibiotic-killed S. aureus induced joint inflammation in mice and elucidated the molecular and cellular mechanism of this type of arthritis. Results: The intraarticular injection of antibiotic-killed S. aureus induced mild to moderate synovitis and bone erosions that lasted for a minimum of 14 days. The frequency and severity of synovitis were significantly reduced in tumor necrosis factor receptor 1 (TNFR1), receptor for Advanced Glycation End Products (RAGE), and toll like receptor 2 (TLR2) knockout mice compared with wild-type animals. The combined depletion of monocytes and neutrophils resulted in a significantly lower frequency of synovitis. Among bacterial factors, insoluble cell debris played a more important role than bacterial DNA or soluble components in inducing joint inflammation. Importantly, anti-TNF therapy abrogated the joint inflammation induced by antibiotic-killed S. aureus. Conclusion: Antibiotic-killed S. aureus induced and maintained the joint inflammation that is mediated through TLR2, TNFR1, and RAGE receptor. The cross-talk between neutrophils and monocytes is responsible for this type of arthritis. Anti-TNF therapy might be used as a novel therapeutic strategy, in combination with antibiotics, to treat staphylococcal septic arthritis. © 2014 American College of Rheumatology.
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2.
  • Ali, Abukar, 1988, et al. (author)
  • CTLA4-Ig but not anti-TNF therapy promotes staphylococcal septic arthritis in mice.
  • 2015
  • In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 212:8, s. 1308-1316
  • Journal article (peer-reviewed)abstract
    • The development of biologics has greatly increased the quality of life as well as the life expectancy of many RA patients. However, a large number of these patients are at an increased risk of developing serious infections. The aim of this study was to examine differential effects of anti-TNF versus CTLA4-Ig treatment on both immunological response and host defense in a murine model of septic arthritis.
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3.
  • Ali, Abukar, 1988, et al. (author)
  • IL-1 Receptor Antagonist Treatment Aggravates Staphylococcal Septic Arthritis and Sepsis in Mice.
  • 2015
  • In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
  • Journal article (peer-reviewed)abstract
    • Interleukin-1 receptor antagonist (IL-1Ra) is the primary therapy against autoinflammatory syndromes with robust efficacy in reducing systemic inflammation and associated organ injury. However, patients receiving IL-1Ra might be at increased risk of acquiring serious infections.
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4.
  • Ammanath, Aparna Viswanathan, et al. (author)
  • From an Hsp90 - binding protein to a peptide drug.
  • 2022
  • In: microLife. - : Oxford University Press (OUP). - 2633-6693. ; 4
  • Journal article (peer-reviewed)abstract
    • The Lpl proteins represent a class of lipoproteins that was first described in the opportunistic bacterial pathogen Staphylococcus aureus, where they contribute to pathogenicity by enhancing F-actin levels of host epithelial cells and thereby increasing S. aureus internalization. The model Lpl protein, Lpl1 was shown to interact with the human heat shock proteins Hsp90α and Hsp90ß, suggesting that this interaction may trigger all observed activities. Here we synthesized Lpl1-derived peptides of different lengths and identified two overlapping peptides, namely, L13 and L15, which interacted with Hsp90α. Unlike Lpl1, the two peptides not only decreased F-actin levels and S. aureus internalization in epithelial cells but they also decreased phagocytosis by human CD14+ monocytes. The well-known Hsp90 inhibitor, geldanamycin, showed a similar effect. The peptides not only interacted directly with Hsp90α, but also with the mother protein Lpl1. While L15 and L13 significantly decreased lethality of S. aureus bacteremia in an insect model, geldanamycin did not. In a mouse bacteremia model L15 was found to significantly decreased weight loss and lethality. Although the molecular bases of the L15 effect is still elusive, in vitro data indicate that simultaneous treatment of host immune cells with L15 or L13 and S. aureus significantly increase IL-6 production. L15 and L13 represent not antibiotics but they cause a significant reduction in virulence of multidrug-resistant S. aureus strains in in vivo models. In this capacity, they can be an important drug alone or additive with other agents.
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5.
  • Baranwal, Gaurav, et al. (author)
  • Impact of cell wall peptidoglycan O-acetylation on the pathogenesis of Staphylococcus aureus in septic arthritis.
  • 2017
  • In: International journal of medical microbiology : IJMM. - : Elsevier BV. - 1618-0607 .- 1438-4221. ; 307:7, s. 388-397
  • Journal article (peer-reviewed)abstract
    • Staphylococcus aureus (S. aureus) is one of the most common pathogen causing septic arthritis. To colonize the joints and establish septic arthritis this bacterium needs to resist the host innate immune responses. Lysozyme secreted by neutrophils and macrophages is an important defense protein present in the joint synovial fluids. S. aureus is known to be resistant to lysozyme due to its peptidoglycan modification by O-acetylation of N-acetyl muramic acid. In this study we have investigated the role of O-acetylated peptidoglycan in septic arthritis. Using mouse models for both local and hematogenous S. aureus arthritis we compared the onset and progress of the disease induced by O-acetyl transferase mutant and the parenteral wild type SA113 strain. The disease progression was assessed by observing the clinical parameters including body weight, arthritis, and functionality of the affected limbs. Further X-ray and histopathological examinations were performed to monitor the synovitis and bone damage. In local S. aureus arthritis model, mice inoculated with the ΔoatA strain developed milder disease (in terms of knee swelling, motor and movement functionality) compared to mice inoculated with the wild type SA113 strain. X-ray and histopathological data revealed that ΔoatA infected mice knee joints had significantly lesser joint destruction, which was accompanied by reduced bacterial load in knee joints. Similarly, in hematogenous S. aureus arthritis model, ΔoatA mutant strain induced significantly less severe clinical septic arthritis compared to its parental strain, which is in accordance with radiological findings. Our data indicate that peptidoglycan O-acetylation plays an important role in S. aureus mediated septic arthritis.
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6.
  • Bergmann, Berglind, et al. (author)
  • Pre-treatment with IL2 gene therapy alleviates Staphylococcus aureus arthritis in mice.
  • 2020
  • In: BMC infectious diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 20:1
  • Journal article (peer-reviewed)abstract
    • Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis.C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage.Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host's ability to clear the infection.Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.
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7.
  • Bokarewa, Maria, 1963, et al. (author)
  • Intraarticular release and accumulation of defensins and bactericidal/permeability-increasing protein in patients with rheumatoid arthritis.
  • 2003
  • In: The Journal of rheumatology. - 0315-162X. ; 30:8, s. 1719-24
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: Defensins and bactericidal/permeability-increasing protein (BPI) are the components of the azurophilic granules of polymorphonuclear cells (PMNC) maintaining antimicrobial protection. Both these substances have been suggested to interact with the host immune system rather than merely kill invading pathogens. We assessed concentrations of BPI and a-defensins in synovial fluid (SF) and matching blood samples of patients with rheumatoid arthritis (RA). METHODS: Matching samples of SF and blood were collected from 67 patients with RA (aged 21-73 yrs) with acute joint effusion. Blood samples from 22 healthy individuals made up a control group. Concentrations of BPI and human neutrophil peptides (HNP 1-3) were measured by ELISA. The results were related to radiological signs of destructive arthritis, duration of the disease, and laboratory markers of inflammation. RESULTS: BPI and HNP concentrations in SF were 10-60 times higher than in matching blood samples (p < 0.0001). Strong correlations between BPI and HNP concentrations were found in both blood and SF. In SF, BPI and HNP concentrations correlated to white blood cell (WBC) count (p < 0.001), and were associated with erosive joint disease (p < 0.05). In contrast, WBC count, serum C-reactive protein, or rheumatoid factor were not significantly correlated to the BPI or HNP concentrations. Serum BPI concentrations were moderately but significantly increased in RA patients compared in blood to controls (p < 0.05). CONCLUSION: BPI and HNP are accumulated in the synovial cavity of patients with RA. Significant correlation between joint erosion and local occurrence of BPI and HNP suggests participation of these molecules in regulation of the destructive course of RA.
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8.
  • Bokarewa, Maria, 1963, et al. (author)
  • Staphylococcus aureus: Staphylokinase
  • 2006
  • In: Int J Biochem Cell Biol. - 1357-2725. ; 38:4, s. 504-9
  • Journal article (peer-reviewed)abstract
    • Staphylokinase is a 136 aa long bacteriophage encoded protein expressed by lysogenic strains of Staphylococcus aureus. Present understanding of the role of staphylokinase during bacterial infection is based on its interaction with the host proteins, alpha-defensins and plasminogen. alpha-Defensins are bactericidal peptides originating from human neutrophils. Binding of staphylokinase to alpha-defensins abolishes their bactericidal properties, which makes staphylokinase a vital tool for staphylococcal resistance to host innate immunity. Complex binding between staphylokinase and plasminogen results in the formation of active plasmin, a broad-spectrum proteolytic enzyme facilitating bacterial penetration into the surrounding tissues. We have recently shown high levels of staphylokinase expression in clinical isolates of skin and mucosal origin and relative low levels in isolates invading internal organs. These findings are supported by sepsis studies using isogenic S. aureus strains demonstrating increased bacterial load in the absence of staphylokinase production. Our observations indicate that staphylokinase favours symbiosis of staphylococci with the host that makes it an important colonization factor.
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9.
  • Boldock, Emma, et al. (author)
  • Human skin commensals augment Staphylococcus aureus pathogenesis.
  • 2018
  • In: Nature microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 3:8, s. 881-90
  • Journal article (peer-reviewed)abstract
    • All bacterial infections occur within a polymicrobial environment, from which a pathogen population emerges to establish disease within a host. Emphasis has been placed on prevention of pathogen dominance by competing microflora acting as probiotics1. Here we show that the virulence of the human pathogen Staphylococcus aureus is augmented by native, polymicrobial, commensal skin flora and individual species acting as 'proinfectious agents'. The outcome is pathogen proliferation, but not commensal. Pathogenesis augmentation can be mediated by particulate cell wall peptidoglycan, reducing the S. aureus infectious dose by over 1,000-fold. This phenomenon occurs using a range of S. aureus strains and infection models and is not mediated by established receptor-mediated pathways including Nod1, Nod2, Myd88 and the NLPR3 inflammasome. During mouse sepsis, augmentation depends on liver-resident macrophages (Kupffer cells) that capture and internalize both the pathogen and the proinfectious agent, leading to reduced production of reactive oxygen species, pathogen survival and subsequent multiple liver abscess formation. The augmented infection model more closely resembles the natural situation and establishes the role of resident environmental microflora in the initiation of disease by an invading pathogen. As the human microflora is ubiquitous2, its role in increasing susceptibility to infection by S. aureus highlights potential strategies for disease prevention.
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10.
  • Deshmukh, Megshree, et al. (author)
  • Gene expression of S100a8/a9 predicts Staphylococcus aureus-induced septic arthritis in mice.
  • 2023
  • In: Frontiers in microbiology. - 1664-302X. ; 14
  • Journal article (peer-reviewed)abstract
    • Septic arthritis is the most aggressive joint disease associated with high morbidity and mortality. The interplay of the host immune system with the invading pathogens impacts the pathophysiology of septic arthritis. Early antibiotic treatment is crucial for a better prognosis to save the patients from severe bone damage and later joint dysfunction. To date, there are no specific predictive biomarkers for septic arthritis. Transcriptome sequencing analysis identified S100a8/a9 genes to be highly expressed in septic arthritis compared to non-septic arthritis at the early course of infection in an Staphylococcus aureus septic arthritis mouse model. Importantly, downregulation of S100a8/a9 mRNA expression at the early course of infection was noticed in mice infected with the S. aureus Sortase A/B mutant strain totally lacking arthritogenic capacity compared with the mice infected with parental S. aureus arthritogenic strain. The mice infected intra-articularly with the S. aureus arthritogenic strain significantly increased S100a8/a9 protein expression levels in joints over time. Intriguingly, the synthetic bacterial lipopeptide Pam2CSK4 was more potent than Pam3CSK4 in inducing S100a8/a9 release upon intra-articular injection of these lipopeptides into the mouse knee joints. Such an effect was dependent on the presence of monocytes/macrophages. In conclusion, S100a8/a9 gene expression may serve as a potential biomarker to predict septic arthritis, enabling the development of more effective treatment strategies.
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11.
  • Elmwall, Jonas, et al. (author)
  • Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus
  • 2017
  • In: Infection and Immunity. - : American Society for Microbiology. - 0019-9567 .- 1098-5522. ; 85:7
  • Journal article (peer-reviewed)abstract
    • Staphylococcus aureus is a major cause of skin and soft tissue infection. The bacterium expresses four major proteases that are emerging as virulence factors: aureolysin (Aur), V8 protease (SspA), staphopain A (ScpA), and staphopain B (SspB). We hypothesized that human galectin-3, a beta-galactoside-binding lectin involved in immune regulation and antimicrobial defense, is a target for these proteases and that proteolysis of galectin-3 is a novel immune evasion mechanism. Indeed, supernatants from laboratory strains and clinical isolates of S. aureus caused galectin-3 degradation. Similar proteolytic capacities were found in Staphylococcus epidermidis isolates but not in Staphylococcus saprophyticus. Galectin-3-induced activation of the neutrophil NADPH oxidase was abrogated by bacterium-derived proteolysis of galectin-3, and SspB was identified as the major protease responsible. The impact of galectin-3 and protease expression on S. aureus virulence was studied in a murine skin infection model. In galectin-3 (+)/(+) mice, SspB-expressing S. aureus caused larger lesions and resulted in higher bacterial loads than protease-lacking bacteria. No such difference in bacterial load or lesion size was detected in galectin-3 (+)/(+) mice, which overall showed smaller lesion sizes than the galectin-3 (+)/(+) animals. In conclusion, the staphylococcal protease SspB inactivates galectin-3, abrogating its stimulation of oxygen radical production in human neutrophils and increasing tissue damage during skin infection.
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12.
  • Fatima, Farah, et al. (author)
  • Radiological features of experimental staphylococcal septic arthritis by micro computed tomography scan.
  • 2017
  • In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 12:2
  • Journal article (peer-reviewed)abstract
    • Permanent joint dysfunction due to bone destruction occurs in up to 50% of patients with septic arthritis. Recently, imaging technologies such as micro computed tomography (μCT) scan have been widely used for preclinical models of autoimmune joint disorders. However, the radiological features of septic arthritis in mice are still largely unknown.NMRI mice were intravenously or intra-articularly inoculated with S. aureus Newman or LS-1 strain. The radiological and clinical signs of septic arthritis were followed for 10 days using μCT. We assessed the correlations between joint radiological changes and clinical signs, histological changes, and serum levels of cytokines.On days 5-7 after intravenous infection, bone destruction verified by μCT became evident in most of the infected joints. Radiological signs of bone destruction were dependent on the bacterial dose. The site most commonly affected by septic arthritis was the distal femur in knees. The bone destruction detected by μCT was positively correlated with histological changes in both local and hematogenous septic arthritis. The serum levels of IL-6 were significantly correlated with the severity of joint destruction.μCT is a sensitive method for monitoring disease progression and determining the severity of bone destruction in a mouse model of septic arthritis. IL-6 may be used as a biomarker for bone destruction in septic arthritis.
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13.
  • Fei, Ying, et al. (author)
  • Commensal Bacteria Augment Staphylococcus aureus septic Arthritis in a Dose-Dependent Manner.
  • 2022
  • In: Frontiers in cellular and infection microbiology. - : Frontiers Media SA. - 2235-2988. ; 12
  • Journal article (peer-reviewed)abstract
    • Septic arthritis is considered one of the most dangerous joints diseases and is mainly caused by the Gram-positive bacterium Staphylococcus aureus (S. aureus). Human skin commensals are known to augment S. aureus infections. The aim of this study was to investigate if human commensals could augment S. aureus-induced septic arthritis.NMRI mice were inoculated with S. aureus alone or with a mixture of S. aureus together with either of the human commensal Staphylococcus epidermidis (S. epidermidis) or Streptococcus mitis (S. mitis). The clinical, radiological and histopathological changes due to septic arthritis were observed. Furthermore, the serum levels of chemokines and cytokines were assessed.Mice inoculated with a mixture of S. aureus and S. epidermidis or S. mitis developed more severe and frequent clinical arthritis compared to mice inoculated with S. aureus alone. This finding was verified pathologically and radiologically. Furthermore, the ability of mice to clear invading bacteria in the joints but not in kidneys was hampered by the bacterial mixture compared to S. aureus alone. Serum levels of monocyte chemoattractant protein 1 were elevated at the early phase of disease in the mice infected with bacterial mixture compared with ones infected with S. aureus alone. Finally, the augmentation effect in septic arthritis development by S. epidermidis was bacterial dose-dependent.The commensal bacteria dose-dependently augment S. aureus-induced septic arthritis in a mouse model of septic arthritis.
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14.
  • Fei, Ying, et al. (author)
  • The combination of a tumor necrosis factor inhibitor and antibiotic alleviates staphylococcal arthritis and sepsis in mice.
  • 2011
  • In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 204:3, s. 348-57
  • Journal article (peer-reviewed)abstract
    • (See the editorial commentary by Chow, on pages 332-4) Background.Despite advances in medical practices, in recent decades permanent reductions in joint function have not been achieved, and the high mortality rate of patients with staphylococcal septic arthritis has not substantially improved. Methods.We evaluated the effects of a combined tumor necrosis factor (TNF) inhibitor and antibiotic therapy on the course of Staphylococcus aureus arthritis and sepsis in mice. Results.Treatment with the combination of a TNF inhibitor and an antibiotic resulted in a quicker relief of clinical arthritis in mice with septic arthritis, compared with an antibiotic monotherapy. Both histopathologically verified synovitis and the extent of joint destruction were reduced by this combined treatment. Importantly, anti-TNF treatment significantly improved the survival rate of mice with S. aureus sepsis and staphylococcal enterotoxin shock syndrome; this effect might be the result of a partial restoration of the hemostatic balance between coagulation and fibrinolysis. Finally, we demonstrated that anti-TNF treatment downregulates high-mobility group protein B1 in staphylococcal enterotoxin shock syndrome. Conclusions.Thus, simultaneous systemic TNF inhibition and antibiotic therapy has beneficial effects on the outcome of S. aureus arthritis and sepsis in a mouse model, suggesting that the combination of a TNF inhibitor and antibiotics represents a novel therapeutic strategy for the treatment of staphylococcal infections.
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15.
  • Gillett, Alan, et al. (author)
  • TNF production in macrophages is genetically determined and regulates inflammatory disease in rats.
  • 2010
  • In: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 185:1, s. 442-50
  • Journal article (peer-reviewed)abstract
    • Dysregulation of TNF is an important pathophysiological phenotype for many diseases. Recently, certain genetically regulated loci have been identified to regulate several inflammatory diseases. We hypothesized that a region on rat chromosome 4 known to regulate experimental autoimmune encephalomyelitis, experimental arthritis and experimental autoimmune neuritis harbors a gene regulating central inflammatory molecules, such as TNF. We therefore mapped TNF production using linkage analysis in the 12th generation of an advanced intercross line between DA and PVG.AV1 rats, which differ in susceptibility to several inflammatory conditions. A single TNF-regulating quantitative trait locus with a logarithm of odds score of 6.2 was identified and its biological effect was confirmed in a congenic rat strain. The profound TNF regulation mapped in congenic strains to the macrophage population. Several TLR signaling cascades led to the same reduced proinflammatory phenotype in congenic macrophages, indicating control of a convergence point for innate inflammatory activity. The decreased TNF potential and reduced proinflammatory macrophage phenotype in congenic rats was also associated with reduced clinical severity in experimental autoimmune encephalomyelitis, pristane-induced arthritis and sepsis experimental models. Determination of genes and mechanisms involved in this genetically determined TNF regulation will be valuable in understanding disease pathogenesis and aid treatment development.
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16.
  • Gupta, Priti, et al. (author)
  • Local Immune Activation and Age Impact on Humoral Immunity in Mice, with a Focus on IgG Sialylation.
  • 2024
  • In: Vaccines. - 2076-393X. ; 12:5
  • Journal article (peer-reviewed)abstract
    • Age alters the host's susceptibility to immune induction. Humoral immunity with circulating antibodies, particularly immunoglobulin G (IgG), plays an essential role in immune response. IgG glycosylation in the fragment crystallizable (Fc) region, including sialylation, is important in regulating the effector function by interacting with Fc gamma receptors (FcγRs). Glycosylation is fundamentally changed with age and inflammatory responses. We aimed to explore the regulation of humoral immunity by comparing responses to antigen-induced immune challenges in young and adult mice using a local antigen-induced arthritis mouse model. This study examines the differences in immune response between healthy and immune-challenged states across these groups. Our initial assessment of the arthritis model indicated that adult mice presented more severe knee swelling than their younger counterparts. In contrast, we found that neither histological assessment, bone mineral density, nor the number of osteoclasts differs. Our data revealed an age-associated but not immune challenge increase in total IgG; the only subtype affected by immune challenge was IgG1 and partially IgG3. Interestingly, the sialylation of IgG2b and IgG3 is affected by age and immune challenges but not stimulated further by immune challenges in adult mice. This suggests a shift in IgG towards a pro-inflammatory and potentially pathogenic state with age and inflammation.
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17.
  • Gupta, Priti, et al. (author)
  • The impact of TLR2 and aging on the humoral immune response to Staphylococcus aureus bacteremia in mice.
  • 2023
  • In: Scientific reports. - 2045-2322. ; 13:1
  • Journal article (peer-reviewed)abstract
    • Aging alters immunoglobulin production, affecting the humoral immune response. Toll-like receptor 2 (TLR2) recognizes Staphylococcus aureus (S. aureus) which causes bacteremia with high mortality in the elderly. To understand how TLR2 and aging affect the humoral immune response in bacteremia, four groups of mice (wild type-young, wild type-old, TLR2-/--young, and TLR2-/--old) were used to analyze immunoglobulin levels in healthy conditions as well as 10days after intravenous injection with S. aureus. We found that aging increased the levels of both IgM and IgG. Increased IgG in aged mice was controlled by TLR2. In bacteremia infection, aged mice failed to mount proper IgM response in both wild-type (WT) and TLR2-/- mice, whereas IgG response was impaired in both aged and TLR2-/- mice. Aged mice displayed reduced IgG1 and IgG2a response irrespective of TLR2 expression. However, impaired IgG2b response was only found in agedWT mice and not in TLR2-/- mice. Both aging and TLR2-/- increased the levels of anti-staphylococcal IgM in bacteremia. Aging increased sialylated IgG in WT mice but not in TLR2-/- mice. IgG sialylation was not affected by the infection in neither of the mice. In summary, aging increases all immunoglobulins except IgG1. However, aged mice fail to mount a proper antibody response to S. aureus bacteremia. TLR2 plays the regulatory role in IgG but not IgM response to infection.
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18.
  • Hanna, Balsam, et al. (author)
  • Osteopenia/osteoporosis develops in the early phase of disease in patients with idiopathic inflammatory myopathies
  • 2021
  • In: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 0300-9742 .- 1502-7732. ; 50:5, s. 398-401
  • Journal article (peer-reviewed)abstract
    • Objective: To study the relationship between different disease-related variables and bone mineral density (BMD) in patients with idiopathic inflammatory myopathies (IIMs). Method: Demographic and clinical data were retrospectively collected from the medical records of all patients diagnosed with IIMs during 2003-2018 in the Rheumatology Department, Sahlgrenska University Hospital, Gothenburg, Sweden. BMD measurements by dual-energy X-ray absorptiometry (DXA) were compared among three patient groups categorized according to the time when DXA was performed in relation to the diagnosis: during the first month, 2-6 months, and 7-24 months after diagnosis. Results: In total, 48 patients were included in the study. BMD correlated positively with body mass index and the presence of myositis-specific autoantibodies. As expected, age and diseases duration had negative associations with BMD. Importantly, osteopenia and osteoporosis were significantly more common in patients who underwent DXA at later time-points of the disease than in those who underwent DXA during the first month after diagnosis. Conclusions: Reduced BMD is common in patients with IIMs. The development of osteopenia/osteoporosis starts in the early phase of myositis (within 6 months), and immediate osteoporosis prophylaxis at diagnosis is necessary.
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19.
  • Hu, Zhicheng, et al. (author)
  • Phenol-soluble modulin α and β display divergent roles in mice with staphylococcal septic arthritis.
  • 2022
  • In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1
  • Journal article (peer-reviewed)abstract
    • Phenol-soluble modulin α (PSMα) is identified as potent virulence factors in Staphylococcus aureus (S. aureus) infections. Very little is known about the role of PSMβ which belongs to the same toxin family. Here we compared the role of PSMs in S. aureus-induced septic arthritis in a murine model using three isogenic S. aureus strains differing in the expression of PSMs (Newman, Δpsmα, and Δpsmβ). The effects of PSMs on neutrophil NADPH-oxidase activity were determined in vitro. We show that the PSMα activates neutrophils via the formyl peptide receptor (FPR) 2 and reduces their NADPH-oxidase activity in response to the phorbol ester PMA. Despite being a poor neutrophil activator, PSMβ has the ability to reduce the neutrophil activating effect of PSMα and to partly reverse the effect of PSMα on the neutrophil response to PMA. Mice infected with S. aureus lacking PSMα had better weight development and lower bacterial burden in the kidneys compared to mice infected with the parental strain, whereas mice infected with bacteria lacking PSMβ strain developed more severe septic arthritis accompanied with higher IL-6 and KC. We conclude that PSMα and PSMβ play distinct roles in septic arthritis: PSMα aggravates systemic infection, whereas PSMβ protects arthritis development.
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20.
  • Hu, Zhicheng, et al. (author)
  • The impact of aging and TLR2 deficiency on the clinical outcomes of Staphylococcus aureus bacteremia.
  • 2023
  • In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 228:3, s. 332-342
  • Journal article (peer-reviewed)abstract
    • Staphylococcus aureus (S. aureus) causes a broad range of infections. TLR2 senses the S. aureus lipoproteins in S. aureus infections. Aging raises the risk of infection. Our aim was to understand how aging and TLR2 impact the clinical outcomes of S. aureus bacteremia. Four groups of mice (Wild type/young, Wild type/old, TLR2-/-/young, and TLR2-/-/old) were intravenously infected with S. aureus, and the infection course was followed. Both TLR2 deficiency and aging enhanced the susceptibility to disease. Increased age was the main contributing factor to mortality and changes in spleen weight, whereas other clinical parameters such as weight loss and kidney abscess formation were more TLR2 dependent. Importantly, aging increased mortality without relying on TLR2. In vitro, both aging and TLR2 deficiency downregulated cytokine/chemokine production of immune cells with distinct patterns. In summary, we demonstrate that aging and TLR2 deficiency impair the immune response to S. aureus bacteremia in distinct ways.
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21.
  • Hu, Zhicheng, et al. (author)
  • Tofacitinib Treatment Suppresses CD4+ T-Cell Activation and Th1 Response, Contributing to Protection against Staphylococcal Toxic Shock.
  • 2024
  • In: International journal of molecular sciences. - 1422-0067. ; 25:13
  • Journal article (peer-reviewed)abstract
    • Staphylococcal toxic shock syndrome (STSS) is a rare, yet potentially fatal disease caused by Staphylococcus aureus (S. aureus) enterotoxins, known as superantigens, which trigger an intense immune response. Our previous study demonstrated the protective effect of tofacitinib against murine toxin-induced shock and a beneficial effect against S. aureus sepsis. In the current study, we examined the effects of tofacitinib on T-cell response in peripheral blood using a mouse model of enterotoxin-induced shock. Our data revealed that tofacitinib suppresses the activation of both CD4+ and CD8+ T cells in peripheral blood. Furthermore, both gene and protein levels of Th1 cytokines were downregulated by tofacitinib treatment in mice with enterotoxin-induced shock. Importantly, we demonstrated that CD4+ cells, but not CD8+ cells, are pathogenic in mice with enterotoxin-induced shock. In conclusion, our findings suggest that tofacitinib treatment suppresses CD4+ T-cell activation and Th1 response, thereby aiding in protection against staphylococcal toxic shock in mice. This insight may guide the future development of novel therapies for STSS.
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22.
  • Jarneborn, Anders, et al. (author)
  • Tofacitinib treatment aggravates Staphylococcus aureus septic arthritis, but attenuates sepsis and enterotoxin induced shock in mice
  • 2020
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
  • Journal article (peer-reviewed)abstract
    • Tofacitinib, a janus kinase inhibitor, is a novel immunosuppressive drug for treatment of rheumatoid arthritis (RA). Septic arthritis (SA) and sepsis caused by Staphylococcus aureus (S. aureus), for which RA patients are at risk, are infections with high mortality. The aim of this study was to investigate the effect of tofacitinib on S. aureus infections using mouse models. In vitro tofacitinib treated mouse splenocytes were stimulated with S. aureus derived stimuli. Mice pre-treated with tofacitinib were inoculated intravenously with either arthritogenic- or septic doses of S. aureus. Arthritis severity and mortality were compared between groups. Additionally, pre-treated mice were challenged with staphylococcal toxin TSST-1 to induce shock. Tofacitinib inhibited splenocyte proliferation and IFN-gamma production in response to TSST-1 and dead S. aureus. In SA, tofacitinib treatment aggravated arthritis with more severe bone erosions. However, in sepsis, treated mice displayed significantly prolonged survival compared to controls. Similarly, in staphylococcal enterotoxin-induced shock tofacitinib pre-treatment, but not late treatment dramatically reduced mortality, which was accompanied by decreased levels of TNF-alpha and IFN-gamma. Our findings show that tofacitinib treatment increase susceptibility of SA in mice, but has a positive effect on survival in S. aureus-induced sepsis and a strong protective effect in toxin-induced shock.
  •  
23.
  • Jin, Tao, 1973, et al. (author)
  • A novel mouse model for septic arthritis induced by Pseudomonas aeruginosa
  • 2019
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
  • Journal article (peer-reviewed)abstract
    • Septic arthritis is one of the most aggressive joint diseases. Although caused predominantly by S. aureus, Gram-negative bacteria, Pseudomonas aeruginosa among them, account for a significant percentage of the causal agents of septic arthritis. However, septic arthritis caused by P. aeruginosa has not been studied thus far, due to lack of an animal model. NMRI mice were inoculated with different doses of P. aeruginosa. The clinical course of septic arthritis and radiological changes of joints were examined. Furthermore, the host molecular and cellular mechanisms involved in P. aeruginosa-induced septic arthritis were investigated. Inoculation of mice with P. aeruginosa caused septic arthritis in a dose-dependent manner. Neutrophil depletion led to higher mortality and more severe joint destruction (p < 0.01). In contrast, monocyte depletion resulted in higher mortality (p < 0.05) but similar arthritis severity compared to controls. Mice depleted of CD4+ T-cells inoculated with P. aeruginosa displayed less severe bone damage (p < 0.05). For the first time, a mouse model for P. aeruginosa septic arthritis is presented. Our data demonstrate that neutrophils play a protective role in P. aeruginosa septic arthritis. Monocytes/macrophages, on the other hand, are only essential in preventing P. aeruginosa-induced mortality. Finally, CD4+ T-cells are pathogenic in P. aeruginosa septic arthritis.
  •  
24.
  • Jin, Tao, 1973, et al. (author)
  • Bacteria and Host Interplay in Staphylococcus aureus Septic Arthritis and Sepsis.
  • 2021
  • In: Pathogens. - : MDPI AG. - 2076-0817. ; 10:2
  • Research review (peer-reviewed)abstract
    • Staphylococcus aureus (S. aureus) infections are a major healthcare challenge and new treatment alternatives are needed. S. aureus septic arthritis, a debilitating joint disease, causes permanent joint dysfunction in almost 50% of the patients. S. aureus bacteremia is associated with higher mortalities than bacteremia caused by most other microbes and can develop to severe sepsis and death. The key to new therapies is understanding the interplay between bacterial virulence factors and host immune response, which decides the disease outcome. S. aureus produces numerous virulence factors that facilitate bacterial dissemination, invasion into joint cavity, and cause septic arthritis. Monocytes, activated by several components of S. aureus such as lipoproteins, are responsible for bone destructions. In S. aureus sepsis, cytokine storm induced by S. aureus components leads to the hyperinflammatory status, DIC, multiple organ failure, and later death. The immune suppressive therapies at the very early time point might be protective. However, the timing of treatment is crucial, as late treatment may aggravate the immune paralysis and lead to uncontrolled infection and death.
  •  
25.
  • Jin, Tao, 1973, et al. (author)
  • Decreased Serum Levels of TGF-β1 are associated with Renal Damages in Female Patients with Systemic Lupus Erythematosus.
  • 2012
  • In: Lupus. - : SAGE Publications. - 1477-0962 .- 0961-2033. ; 21:3, s. 310-318
  • Journal article (peer-reviewed)abstract
    • Introduction: Transforming growth factor β1 (TGF-β1) has a large role in the control of autoimmunity. TGF-β1 production by lymphocytes is reduced in systemic lupus erythematosus (SLE). Decreased levels of TGF-β1 might associate to disease susceptibility, activity and organ damage in SLE. However, the correlation between TGF-β1 levels and severity of renal damage in SLE has not been examined. Methods: The present study was undertaken to assess the serum levels of total and active TGF-β1 in 150 female patients with SLE and 31 healthy women. Simple and multiple regression analyses between TGF-β1 levels and the diseases-related variables were performed in patients with SLE. Results: Serum levels of both total and active TGF-β1 were significantly reduced in patients with SLE compared with levels in healthy controls (p < 0.01). Total TGF-β1 levels correlated positively with white blood cell, platelet counts, calculated glomerular filtration rate (GFR), and active TGF-β1 level, and inversely with erythrocyte sedimentation rate (ESR). In multiple regression analysis, ESR and platelet counts remained determinants of total TGF-β1. Total TGF-β1 levels were lower in patients with high disease activity (SLEDAI > 10) and severe organ damage (SLICC > 3). Significantly lower levels of total TGF-β1 were found in patients with severe renal damage, i.e. lower TGF-β1 in patients with 24-h urine protein over 3.5 g than in those with below 3.5 g (p < 0.05); lower TGF-β1 in patients with GFR less than 50 ml/min than in those with over 50 ml/min (p < 0.05). In contrast, active TGF-β1 only correlated with platelet counts. There was no association between renal damage and the levels of active TGF-β1. Conclusion: This study demonstrates significantly reduced serum levels of both total and active TGF-β1 in women with SLE compared with healthy women. Total TGF-β1 levels are correlated negatively with ESR and positively with blood platelets. Total TGF-β1 levels were lower in SLE patients with high disease activity and severe organ damage. Importantly, the severity of the renal damage was associated with decreased serum levels of total TGF-β1, suggesting that TGF-β1 might be involved in pathogenesis of renal damage caused by lupus nephritis.
  •  
26.
  • Jin, Tao, 1973 (author)
  • Exploring the role of bacterial virulence factors and host elements in septic arthritis: insights from animal models for innovative therapies.
  • 2024
  • In: Frontiers in microbiology. - 1664-302X. ; 15
  • Research review (peer-reviewed)abstract
    • Septic arthritis, characterized as one of the most aggressive joint diseases, is primarily attributed to Staphylococcus aureus (S. aureus) and often results from hematogenous dissemination. Even with prompt treatment, septic arthritis frequently inflicts irreversible joint damage, leading to sustained joint dysfunction in a significant proportion of patients. Despite the unsatisfactory outcomes, current therapeutic approaches for septic arthritis have remained stagnant for decades. In the clinical context, devising innovative strategies to mitigate joint damage necessitates a profound comprehension of the pivotal disease mechanisms. This entails unraveling how bacterial virulence factors interact with host elements to facilitate bacterial invasion into the joint and identifying the principal drivers of joint damage. Leveraging animal models of septic arthritis emerges as a potent tool to achieve these objectives. This review provides a comprehensive overview of the historical evolution and recent advancements in septic arthritis models. Additionally, we address practical considerations regarding experimental protocols. Furthermore, we delve into the utility of these animal models, such as their contribution to the discovery of novel bacterial virulence factors and host elements that play pivotal roles in the initiation and progression of septic arthritis. Finally, we summarize the latest developments in novel therapeutic strategies against septic arthritis, leveraging insights gained from these unique animal models.
  •  
27.
  • Jin, Tao, 1973, et al. (author)
  • Fatal outcome of bacteraemic patients caused by infection with staphylokinase-deficient Staphylococcus aureus strains.
  • 2003
  • In: Journal of medical microbiology. - 0022-2615. ; 52:Pt 10, s. 919-23
  • Journal article (peer-reviewed)abstract
    • Staphylokinase (SAK) is a plasminogen-activator protein produced by Staphylococcus aureus. SAK production was evaluated in vitro in S. aureus isolates from the bloodstream of patients with lethal (n = 56) and non-lethal (n = 57) bacteraemia and from anterior nares of healthy subjects (n = 48). Most isolates (93/161) produced SAK, and 68 % of SAK-producing isolates expressed both surface-bound and secreted types of SAK. SAK production was significantly less common among isolates from patients with lethal bacteraemia (39 %) than isolates from patients with non-lethal bacteraemia (68 %) or nasal carriage isolates (67 %) (P < 0.01). After adjusting for infection with methicillin-resistant S. aureus and APACHE II score, patients infected with SAK-deficient isolates were 4.3 times more likely to have lethal bacteraemia than patients whose infecting isolate produced high levels of SAK (> or =5 microg ml(-1)), suggesting that in vitro SAK production was inversely associated with clinical outcome among patients with S. aureus bacteraemia. The high frequency of SAK production in nasal isolates and in cases with uncomplicated bacteraemia suggests that SAK may be one of the adaptive mechanisms of S. aureus symbiosis with the host.
  •  
28.
  • Jin, Tao, 1973, et al. (author)
  • Impact of short-term therapies with biologics on prothrombotic biomarkers in rheumatoid arthritis.
  • 2009
  • In: Clinical and experimental rheumatology. - 0392-856X. ; 27:3, s. 491-4
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Imbalance of haemostasis in patients with rheumatoid arthritis (RA) contributes to future risk of cardiovascular diseases (CVD). Prothrombotic molecules, e.g. fibrinogen, D-dimer, and tPA are elevated in plasma of RA patients, being associated to CVD. There is no imformation about the influence of biological drugs, e.g. anti-CD20 and tumor necrosis factor (TNF) antibodies on these prothrombotic molecules. OBJECTIVE: To assess whether anti-TNF and anti-CD20 therapies modify the profiles of cardiovascular risk factors in patients with RA. METHODS: The expression of prothrombotic molecules in plasma was investigated in 10 RA patients before and after treatment with TNF-alpha antibodies and in another 12 RA patients before and after anti-CD20 treatment. RESULTS: Both anti-TNF and anti-CD20 infusions gave rise to clear clinical improvement. However, only anti-CD20 infusion significantly (p=0.05) reduced concentration of fibrinogen (p=0.05), D-dimer (p<0.001), as well as tPA levels (p<0.01). In contrast, in TNF antibody treated patients only tPA levels were significantly decreased following the treatment (p<0.05). CONCLUSIONS: Infusion of CD20 antibodies to the patients with active RA led to a clearly reduced plasma levels of predictors of CVD indicating that this treatment, apart from its anti-inflammatory properties, may reduce the risk for future CVD in RA.
  •  
29.
  •  
30.
  • Jin, Tao, 1973, et al. (author)
  • Soluble E-cadherin in systemic lupus erythematosus.
  • 2013
  • In: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 40:10, s. 1677-82
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: E-cadherin is a potent adherens junction molecule implicated in tissue morphogenesis, epithelial functioning, and immune regulation. Serum levels of soluble E-cadherin (sE-cadherin), an end product of proteolytic cleavage of E-cadherin, is increased in patients with cancer, infections, and inflammation-related diseases. The aim of our study was to measure serum levels of sE-cadherin in systemic lupus erythematosus (SLE) and to determine associations between serum levels of sE-cadherin and markers of inflammation and organ damage in female patients with SLE.METHODS: Serum levels of sE-cadherin were analyzed by ELISA in 150 female patients with SLE and 31 healthy women. Simple and multiple regression analyses between sE-cadherin levels and disease-related variables were performed in patients with SLE.RESULTS: Serum levels of sE-cadherin were elevated in patients with SLE compared with levels in healthy controls. sE-cadherin levels correlated positively with age, disease duration, SLE Collaborating Clinics Damage Index, erythrocyte sedimentation rate (ESR), s-creatinine, cholesterol, triglycerides, interleukin 6, and matrix metalloproteinase-3. In multiple regression analysis, s-creatinine, age, ESR, and triglycerides remained determinants of sE-cadherin. Within the patients with SLE, higher sE-cadherin levels were found only in patients with renal damage, i.e., s-creatinine > 90 μmol/l, glomerular filtration rate < 50 ml/min, or renal involvement ever by SLE.CONCLUSION: Our study demonstrates significantly elevated serum levels of sE-cadherin in women with SLE compared with healthy women. The levels of sE-cadherin were positively correlated to s-creatinine, age, ESR, and triglycerides. Significantly elevated sE-cadherin levels were observed only in patients with renal damage.
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31.
  • Jin, Tao, 1973, et al. (author)
  • Staphylococcus aureus resists human defensins by production of staphylokinase, a novel bacterial evasion mechanism
  • 2004
  • In: J Immunol. - 0022-1767. ; 172:2, s. 1169-76
  • Journal article (peer-reviewed)abstract
    • Alpha-defensins are peptides secreted by polymorphonuclear cells and provide antimicrobial protection mediated by disruption of the integrity of bacterial cell walls. Staphylokinase is an exoprotein produced by Staphylococcus aureus, which activates host plasminogen. In this study, we analyzed the impact of interaction between alpha-defensins and staphylokinase on staphylococcal growth. We observed that staphylokinase induced extracellular release of alpha-defensins from polymorphonuclear cells. Moreover, a direct binding between alpha-defensins and staphylokinase was shown to result in a complex formation. The biological consequence of this interaction was an almost complete inhibition of the bactericidal effect of alpha-defensins. Notably, staphylokinase with blocked plasminogen binding site still retained its ability to neutralize the bactericidal effect of alpha-defensins. In contrast, a single mutation of a staphylokinase molecule at position 74, substituting lysine for alanine, resulted in a 50% reduction of its alpha-defensin-neutralizing properties. The bactericidal properties of alpha-defensins were tested in 19 S. aureus strains in vitro and in a murine model of S. aureus arthritis. Staphylococcal strains producing staphylokinase were protected against the bactericidal effect of alpha-defensins. When staphylokinase was added to staphylokinase-negative S. aureus cultures, it almost totally abrogated the effect of alpha-defensins. Finally, human neutrophil peptide 2 injected intra-articularly along with bacteria alleviated joint destruction. In this study, we report a new property of staphylokinase, its ability to induce secretion of defensins, to complex bind them and to neutralize their bactericidal effect. Staphylokinase production may therefore be responsible in vivo for defensin resistance during S. aureus infections.
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32.
  • Jin, Tao, 1973, et al. (author)
  • Staphylokinase reduces plasmin formation by endogenous plasminogen activators.
  • 2008
  • In: European journal of haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 81:1, s. 8-17
  • Journal article (peer-reviewed)abstract
    • Hyperfibrinolysis is a consequence of imbalance between fibrinolytic activators and their inhibitors. Increased levels of circulating plasminogen (Plg) activators such as tissue- or urokinase-type plasminogen activators (tPA or uPA respectively) are the most common causes of hyperfibrinolysis, occasionally causing major hemorrhages. We found that staphylokinase (SAK), a well-known Plg activator of bacterial origin, inhibits Plg activation mediated by endogenous tPA and uPA. Furthermore, mixture of SAK with tPA led to a significantly reduced Plg-dependent fibrinolysis. This inhibitory effect was exerted through direct action of SAK on Plg rather than indirectly on tPA or uPA. Inhibition of Plg activation by SAK is readily abrogated by interaction of SAK with human neutrophil peptides (HNPs). Finally, we show that NH2-terminal residues of SAK are important for the inhibitory effect of SAK on tPA- and uPA-mediated Plg activation. In conclusion, SAK reduces tPA/uPA-mediated Plg activation by means of SAK.Plg complex formation, consequently downregulating tPA/uPA-induced fibrinolysis.
  •  
33.
  • Jin, Tao, 1973, et al. (author)
  • The role of urokinase in innate immunity against Staphylococcus aureus
  • 2005
  • In: Microbes Infect. - : Elsevier BV. - 1286-4579. ; 7:9-10, s. 1170-5
  • Journal article (peer-reviewed)abstract
    • Urokinase (uPA) is a serine protease that not only displays fibrinolytic function but also promotes host leukocytes to home to inflammatory sites. We have recently demonstrated that staphylokinase (SAK), which is a fibrinolytic protein secreted by Staphylococcus aureus, forms complexes with human neutrophil peptides (HNPs), which are members of the defensin family and have anti-microbial properties, thereby inhibiting the bactericidal effects of the HNPs. The aim of this study was to assess whether endogenous uPA, which has fibrinolytic properties similar to those of SAK, binds to HNPs and interferes with SAK/HNPs interaction. To this end, an ELISA was used to analyze the interactions between uPA and HNPs. HMW uPA had the ability to bind to both HNP types. The biological consequences of the formation of this complex were analyzed with respect to its bactericidal properties. HMW uPA killed S. aureus, albeit at relatively high doses (50-100 mug/ml). In contrast, the binding of HMW uPA to HNPs had no impact on the bactericidal functions of the HNPs. Importantly, the addition of HMW uPA to SAK eliminated the ability of SAK to neutralize HNPs. Our results demonstrate that endogenous HMW uPA inhibits S. aureus growth both directly, by cytolysis, and indirectly, by abrogation of the neutralizing effect of SAK on the bactericidal activities of HNPs. These findings indicate novel functions of HMW uPA in the host defense against staphylococcal infections.
  •  
34.
  • Jin, Tao, 1973, et al. (author)
  • Urokinase, a constitutive component of the inflamed synovial fluid, induces arthritis.
  • 2003
  • In: Arthritis research & therapy. - 1478-6362. ; 5:1
  • Journal article (peer-reviewed)abstract
    • Urokinase plasminogen activator (uPA) is an important regulator of fibrinolysis in synovial fluid. An increase of uPA activity and expression of its receptor have been reported in joints of patients with rheumatoid arthritis (RA). The aim of the present study was to assess the arthritogenic capacity of uPA and the mechanisms by which this effect is mediated. uPA was injected into the knee joints of healthy mice, and morphological signs of arthritis were assessed 4 days after the injection. The prerequisite of different leukocyte populations for the development of uPA-triggered arthritis was assessed by selective cell depletion. The inflammatory capacity of uPA was assessed in vitro. Finally, levels of uPA were measured in 67 paired blood and synovial fluid samples from RA patients. The synovial fluid from RA patients displayed higher levels of uPA compared with blood samples. Morphological signs of arthritis were found in 72% of uPA-injected joints compared with in only 18% of joints injected with PBS (P < 0.05). Synovitis was characterised by infiltration of CD4-Mac-1+ mononuclear cells, by the formation of pannus and by occasional cartilage destruction. The absence of monocytes and lymphocytes diminished the frequency of synovitis (P < 0.01), indicating an arthritogenic role of both these leukocyte populations. Synthetic uPA inhibitor downregulated the incidence of uPA-triggered arthritis by 50%. uPA induced arthritis, stimulating the release of proinflammatory cytokines IL-6, IL-1beta and tumour necrosis factor alpha. Accumulation of uPA locally in the joint cavity is a typical finding in erosive RA. uPA exerts potent arthritogenic properties and thus may be viewed as one of the essential mediators of joint inflammation.
  •  
35.
  • Jin, Tao, 1973, et al. (author)
  • Urokinase-type plasminogen activator, an endogenous antibiotic
  • 2005
  • In: J Infect Dis. - 0022-1899. ; 192:3, s. 429-37
  • Journal article (peer-reviewed)abstract
    • Urokinase-type plasminogen activator (uPA) is a serine protease that not only displays fibrinolytic function but also modulates innate and adaptive immune responses. In the present study, we assessed whether uPA acts as an endogenous antibiotic. It has been demonstrated that uPA inhibits growth of Staphylococcus aureus both in vivo and in vitro. Importantly, the bactericidal properties of uPA are associated with the serine protease domain of the molecule but are not dependent on its plasminogen-activation potential and cannot be inhibited by plasminogen activator inhibitor type 1 (PAI-1). In a murine infection model, uPA treatment alleviated staphylococcal sepsis by inhibiting bacterial growth. To further evaluate the changes in uPA levels during the course of staphylococcal infection, total uPA and active uPA levels were analyzed in plasma and in kidney homogenates. Expression of total uPA was constant, but PAI-1 levels were dramatically increased in plasma and in kidney homogenates during the course of staphylococcal infection. After infection with staphylococci, the level of metabolically active uPA was unaltered in plasma but was significantly decreased in kidney homogenates. Active uPA levels were inversely related to PAI-1 levels and to bacterial loads in kidney homogenates. In conclusion, we report that uPA acts as an endogenous antibacterial substance that might constitute the first line of host defense against staphylococcal infection. The decreased active uPA levels in infected organs might be due to the dramatically increased PAI-1 production during S. aureus infection.
  •  
36.
  • Kłak, Marcin, et al. (author)
  • Tranexamic acid, an inhibitor of plasminogen activation, aggravates staphylococcal septic arthritis and sepsis.
  • 2010
  • In: Scandinavian journal of infectious diseases. - : Informa UK Limited. - 1651-1980 .- 0036-5548. ; 42:5, s. 351-358
  • Journal article (peer-reviewed)abstract
    • Abstract Haemostatic balance shifts towards pro-coagulation during infection. Plasminogen, a key molecule of fibrinolysis, may play an important role in the pathogenesis of staphylococcal infections. In the present study, we assessed the impact of inhibition of plasminogen activation by tranexamic acid on the course of staphylococcal sepsis and septic arthritis in mice. We found significantly down-regulated plasmin activity and increased D-dimer levels in the blood from the mice with staphylococcal sepsis. Treatment with tranexamic acid significantly increased the severity and mortality of staphylococcal infection. In addition, tranexamic acid reduced the survival rate in a murine model for staphylococcal enterotoxin A-induced death. The aggravation of diseases by tranexamic acid was due neither to the pro-inflammatory cytokine network, nor to impairment of bacterial clearance. Modulation of fibrinolysis, either by supplement of fibrinolytic molecules (tissue plasminogen activator or plasmin) or by fibrinogen depletion, did not reduce the mortality of staphylococcal sepsis. In conclusion, we report that treatment with tranexamic acid led to distinct aggravation of staphylococcal septic arthritis and sepsis in mice, suggesting the clinical importance of fibrinolytic balance in staphylococcal infection.
  •  
37.
  • Kopparapu, Pradeep Kumar, et al. (author)
  • Lipoproteins Are Responsible for the Pro-Inflammatory Property of Staphylococcus aureus Extracellular Vesicles
  • 2021
  • In: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 22:13
  • Journal article (peer-reviewed)abstract
    • Staphylococcal aureus (S. aureus), a Gram-positive bacteria, is known to cause various infections. Extracellular vesicles (EVs) are a heterogeneous array of membranous structures secreted by cells from all three domains of life, i.e., eukaryotes, bacteria, and archaea. Bacterial EVs are implied to be involved in both bacteria-bacteria and bacteria-host interactions during infections. It is still unclear how S. aureus EVs interact with host cells and induce inflammatory responses. In this study, EVs were isolated from S. aureus and mutant strains deficient in either prelipoprotein lipidation (Delta lgt) or major surface proteins (Delta srtAB). Their immunostimulatory capacities were assessed both in vitro and in vivo. We found that S. aureus EVs induced pro-inflammatory responses both in vitro and in vivo. However, this activity was dependent on lipidated lipoproteins (Lpp), since EVs isolated from the Delta lgt showed no stimulation. On the other hand, EVs isolated from the Delta srtAB mutant showed full immune stimulation, indicating the cell wall anchoring of surface proteins did not play a role in immune stimulation. The immune stimulation of S. aureus EVs was mediated mainly by monocytes/macrophages and was TLR2 dependent. In this study, we demonstrated that not only free Lpp but also EV-imbedded Lpp had high pro-inflammatory activity.
  •  
38.
  •  
39.
  • Krzyzowska, Malgorzata, et al. (author)
  • Tofacitinib treatment in primary herpes simplex encephalitis interferes with anti-viral response.
  • 2022
  • In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 225:9, s. 1545-1553
  • Journal article (peer-reviewed)abstract
    • Tofacitinib, a Janus kinase inhibitor, is a novel immunosuppressive drug for treatment of rheumatoid arthritis (RA). Herpes simplex virus type 1 (HSV-1) may cause encephalitis during primary infection or following reactivation from a latent state. Long-term tofacitinib treatment may increase the risk of this life-threatening condition. The aim of this study was to investigate the effect of tofacitinib on HSV-1 primary infection using a mouse model. Mice pre-treated with tofacitinib were intranasally infected with a clinical strain of HSV-1 and monitored for infection severity and anti-viral response. Tofacitinib treatment of HSV-1 primary infection resulted in increased viral loads and worsened clinical outcome. Furthermore, tofacitinib promoted M2 anti-inflammatory phenotype of microglia and infiltrating monocytes as well as inhibited production of inflammatory and antiviral cytokines by macrophages in vitro. Our findings show that treatment with tofacitinib increases severity of HSE in mice, by impairing anti-viral response induced by monocytes and microglia.
  •  
40.
  • Kwiecinski, Jakub, 1985, et al. (author)
  • Activation of plasminogen by staphylokinase reduces the severity of Staphylococcus aureus systemic infection.
  • 2010
  • In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 202:7, s. 1041-9
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Staphylokinase (SAK) is produced by the majority of Staphylococcus aureus strains. It is an extracellular protein that activates the conversion of human plasminogen (plg) to plasmin. The role played by SAK in staphylococcal infection is unclear. METHODS: Wild-type S. aureus strain LS-1, which lacks the ability to produce SAK, was modified by an insertion of the sak gene into its chromosome. The sak gene was integrated in 2 forms--(1) linked to its own promoter and (2) fused to the promoter of the protein A gene--which resulted in the overexpression of SAK. SAK is highly specific for human plg and exhibits almost no activity toward murine plg. To investigate the role played by SAK in a murine infection model, human plg transgenic mice and their wild-type counterparts were inoculated intravenously with congenic S. aureus strains differing in SAK production. RESULTS: Human plg transgenic mice inoculated with SAK-expressing strains displayed significantly reduced mortality, less weight loss, and lower bacterial loads in kidneys than did the wild-type mice. No difference in the severity of sepsis was observed between transgenic and wild-type mice infected with a SAK-deficient strain. CONCLUSIONS: The results suggest that expression of SAK followed by activation of plg alleviates the course of S. aureus sepsis.
  •  
41.
  • Kwiecinski, Jakub, 1985, et al. (author)
  • Biofilm formation by Staphylococcus aureus clinical isolates correlates with the infection type.
  • 2019
  • In: Infectious diseases. - : Informa UK Limited. - 2374-4243 .- 2374-4235. ; 51:6, s. 446-451
  • Journal article (peer-reviewed)abstract
    • Biofilms are involved in many Staphylococcus aureus infections, but relation of biofilm formation and the infection types or the clinical outcomes remain unclear.We measured biofilm formation, with a microtiter plate assay, of a collection of methicillin-sensitive clinical isolates from 159 invasive S. aureus infections, encompassing all cases occurring within a hospital catchment area during two years, and from additional 49 non-invasive skin infections from the same region. Results were related to available clinical and microbiological documentation.Isolates from medical device infections (intravenous line-associated and prosthetic joint infections), as well as isolates from superficial skin infections, were particularly proficient in forming biofilms. No increased biofilm-forming capacity was seen in isolates from endocarditis, osteomyelitis, or other infections. There was also a correlation of biofilm formation with the agr type of the isolates. Thicker biofilms were more resistant to antibiotic treatment in vitro. No correlation between biofilm formation and clinical outcomes was noted.S. aureus isolates from 'classical' biofilm-related infections, but also from superficial skin infections, are especially proficient in forming biofilms. There is, however, no obvious relation of biofilm-forming capacity of isolates and the clinical outcome of the infection, and more studies on this issue are needed.
  •  
42.
  • Kwiecinski, Jakub, 1985, et al. (author)
  • Biofilm Formation by Staphylococcus aureus Isolates from Skin and Soft Tissue Infections.
  • 2015
  • In: Current microbiology. - : Springer Science and Business Media LLC. - 1432-0991 .- 0343-8651. ; 70:5, s. 698-703
  • Journal article (peer-reviewed)abstract
    • Many diseases caused by Staphylococcus aureus are associated with biofilm formation. However, the ability of S. aureus isolates from skin and soft tissue infections to form biofilms has not yet been investigated. We tested 160 isolates from patients with various skin infections for biofilm-forming capacity in different growth media. All the isolates formed biofilms, the extent of which depended on the type of growth medium. The thickest biofilms were formed when both plasma and glucose were present in the broth; in this case, S. aureus incorporated host fibrin into the biofilm's matrix. There were no differences in the biofilm formation between isolates from different types of skin infections, except for a particularly good biofilm formation by isolates from diabetic wounds and a weaker biofilm formation by isolates from impetigo. In conclusion, biofilm formation is a universal behavior of S. aureus isolates from skin infections. In some cases, such as in diabetic wounds, a particularly strong biofilm formation most likely contributes to the chronic and recurrent character of the infection. Additionally, as S. aureus apparently uses host fibrin as part of the biofilm structure, we suggest that plasma should be included more frequently in in vitro biofilm studies.
  •  
43.
  • Kwiecinski, Jakub, 1985, et al. (author)
  • Fibrinolysis is down-regulated in mouse collagen-induced arthritis, but its normalization does not alleviate the course of disease.
  • 2011
  • In: Inflammation research : official journal of the European Histamine Research Society ... [et al.]. - : Springer Science and Business Media LLC. - 1420-908X. ; 60:11, s. 1021-1029
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: Down-regulation of fibrinolysis and increased fibrin deposition in joints are hallmarks of rheumatoid arthritis (RA), and are believed to be involved in disease progression. The mouse model of collagen-induced arthritis (CIA) closely resembles RA and has been used to explore mechanism and treatments of RA, but neither the fibrinolytic system nor pro-fibrinolytic therapies were investigated in CIA. MATERIALS AND METHODS: Plasmin activity, levels of plasminogen activator inhibitor (PAI-1), D-dimer, and IL-6 were measured in plasma of CIA mice. Fibrin deposition and PAI-1 levels were also measured in inflamed joints. Mice were treated with plasminogen activators uPA (urokinase-type plasminogen activator) or tPA (tissue-type plasminogen activator). Effects of treatment on disease severity and fibrinolytic system were assessed. RESULTS: CIA caused decrease in plasmin activity, accompanied by increase in PAI-1 levels, in both blood and inflamed joints. This resulted in massive fibrin deposition in synovium. PAI-1 levels correlated negatively with plasmin activity and positively with IL-6. Treatments with uPA and tPA improved plasmin activity and removed fibrin deposits in inflamed joints. However, disease severity remained unchanged. CONCLUSIONS: Fibrinolytic changes in CIA parallel changes in RA, making CIA a suitable model to study fibrinolysis in RA. Normalization of plasmin activity in CIA after treatment with plasminogen activators had no effect on disease severity.
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44.
  • Kwiecinski, Jakub, 1985, et al. (author)
  • Relationship between elevated cerebrospinal fluid levels of plasminogen activator inhibitor 1 and neuronal destruction in patients with neuropsychiatric systemic lupus erythematosus.
  • 2009
  • In: Arthritis and rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:7, s. 2094-101
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: A homeostatic imbalance between coagulation and fibrinolysis might occur intrathecally in neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no published data on levels of fibrinolytic factors in the cerebrospinal fluid (CSF) of patients with NPSLE. The present study was undertaken to assess CSF levels of fibrinolytic molecules, including urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), D-dimer, and plasminogen activator inhibitor 1 (PAI-1), in SLE patients with clinically verified neuropsychiatric involvement and to compare these levels with those in SLE patients without neuropsychiatric involvement and in healthy subjects. METHODS: Levels of uPA, tPA, and PAI-1 were assessed in CSF from 94 patients with SLE (33 who had NPSLE, 56 who did not have NPSLE, and 5 who were positive for antiphospholipid antibody [not included in the NPSLE or non-NPSLE group]) and from 53 age-matched controls. Patients were evaluated clinically, with magnetic resonance imaging of the brain, analyses of neuronal/glial degradation products in CSF, and neuropsychiatric testing. RESULTS: In the group of patients with NPSLE, intrathecal PAI-1 levels were significantly elevated compared with levels in SLE patients without overt neuropsychiatric involvement (P < 0.05) and in healthy controls (P < 0.001). In contrast, intrathecal levels of uPA did not differ significantly. Intrathecal levels of PAI-1 correlated significantly with CSF levels of interleukin-6 (IL-6) (r = 0.34, P < 0.001) and IL-8 (r = 0.33, P < 0.001). Importantly, increased PAI-1 and D-dimer levels were observed in SLE patients who had pathologically elevated levels of glial fibrillary acidic protein, neurofilament triplet protein, and tau protein in CSF. CONCLUSION: Intrathecal release of PAI-1 is increased in patients with NPSLE. This results in impaired fibrinolysis, which might contribute to neuronal and astrocytic damage in NPSLE.
  •  
45.
  • Kwiecinski, Jakub, 1985, et al. (author)
  • Reply to Bouchiat et al.
  • 2014
  • In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 210:8, s. 1343-1344
  • Journal article (other academic/artistic)abstract
    • Comment on: Buchiat Bouchiat C, Mehenni C, Meugnier H, Bes M, Tristan A, Vandenesch F. Limitations of staphylokinase as a marker for Staplylococcus aureus invasive infections in humans. J Infect Dis 2014;210:1341-3
  •  
46.
  • Kwiecinski, Jakub, 1985, et al. (author)
  • Staphylokinase controls Staphylococcus aureus biofilm formation and detachment through host plasminogen activation.
  • 2016
  • In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 213:1, s. 139-148
  • Journal article (peer-reviewed)abstract
    • Staphylococcus aureus biofilms, a leading cause of persistent infections, are highly resistant to immune defenses and antimicrobial therapies. In this study, we investigated the contribution of fibrin and staphylokinase to biofilm formation. Both in clinical S. aureus isolates and in laboratory strains, high staphylokinase-producing strains formed less biofilm than strains that lacked staphylokinase, suggesting that staphylokinase prevents biofilm formation. Additionally, staphylokinase induced detachment of mature biofilms. This effect depended on plasminogen activation by staphylokinase. Host-derived fibrin, the main substrate cleaved by staphylokinase-activated plasminogen, was a major component of biofilm matrix and dissolution of this fibrin scaffold greatly increased susceptibility of biofilms to antibiotics and neutrophil phagocytosis. Staphylokinase also attenuated biofilm-associated catheter infections in mouse models. In conclusion, our results reveal a novel role for staphylokinase-induced plasminogen activation that prevents S. aureus biofilm formation and induces detachment of existing biofilms through proteolytic cleavage of biofilm matrix components.
  •  
47.
  • Kwiecinski, Jakub, 1985, et al. (author)
  • Staphylokinase Promotes the Establishment of Staphylococcus aureus Skin Infections While Decreasing Disease Severity
  • 2013
  • In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 208:6, s. 990-999
  • Journal article (peer-reviewed)abstract
    • Skin infections are frequently caused by Staphylococcus aureus and can lead to a fatal sepsis. The microbial mechanisms controlling the initiation and progression from mild skin infection to a severe disseminated infection remain poorly understood. Using a combination of clinical data and in vitro and ex vivo assays, we show that staphylokinase, secreted by S. aureus, promoted the establishment of skin infections in humans and increased bacterial penetration through skin barriers by activating plasminogen. However, when infection was established, the interaction between staphylokinase and plasminogen did not promote systemic dissemination but induced the opening and draining of abscesses and decreased disease severity in neutropenic mice. Also, increased staphylokinase production was associated with noninvasive S. aureus infections in patients. Our results point out the dual roles of staphylokinase in S. aureus skin infections as promoting the establishment of infections while decreasing disease severity.
  •  
48.
  • Kwiecinski, Jakub, 1985, et al. (author)
  • Sulfatide attenuates experimental Staphylococcal aureus sepsis through a CD1d-dependent pathway.
  • 2013
  • In: Infection and immunity. - 1098-5522. ; 81:4, s. 1114-1120
  • Journal article (peer-reviewed)abstract
    • Natural killer T (NKT) lymphocytes are implicated in the early response to microbial infection. Further, sulfatide, a myelin self-glycosphingolipid, activates a type II NKT cell subset, and can modulate disease in murine models. We examined the role of NKT cells and the effect of sulfatide treatment in a murine model of Staphylococcus aureus sepsis. Lack of CD1d-restricted NKT cells did not alter survival after a lethal inoculum of S. aureus. In contrast, sulfatide treatment significantly improved the survival rate of mice with S. aureus sepsis, accompanied by decreased levels of TNF-α and IL-6 in the blood. The protective effect of sulfatide treatment depended on CD1d, but not on type I NKT cells, suggesting that activation of type II NKT cells by sulfatide has beneficial effects on the outcome of S. aureus sepsis in this model.
  •  
49.
  • Kwiecinski, Jakub, 1985, et al. (author)
  • Surface proteins of Staphylococcus aureus play an important role in experimental skin infection.
  • 2014
  • In: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. - : Wiley. - 1600-0463. ; 122:12, s. 1240-1250
  • Journal article (peer-reviewed)abstract
    • Staphylococcus aureus is the most common cause of skin infections that range from mild diseases up to life-threatening conditions. Mechanisms of S. aureus virulence in those infections remain poorly studied. To investigate the impact of S. aureus surface proteins on skin infection, we used mouse models of skin abscess formation and skin necrosis, induced by a subcutaneous injection of bacteria. In the skin abscess model, a sortase-deficient S. aureus strain lacking all of its cell-wall anchored proteins was less virulent than its wild-type strain. Also, strains specifically lacking protein A, fibronecting binding proteins, clumping factor A or surface protein SasF were impaired in their virulence. When a model of dermonecrosis was studied, the S. aureus surface proteins could not be shown to be involved. In summary, surface proteins play an important role in virulence of S. aureus skin abscess infections, but not in formation of skin necrosis.
  •  
50.
  • Kwiecinski, Jakub, 1985, et al. (author)
  • Tissue Plasminogen Activator Coating on Implant Surfaces Reduces Staphylococcus aureus Biofilm Formation
  • 2016
  • In: Applied and Environmental Microbiology. - : American Society for Microbiology. - 0099-2240 .- 1098-5336. ; 82:1, s. 394-401
  • Journal article (peer-reviewed)abstract
    • Staphylococcus aureus biofilm infections of indwelling medical devices are a major medical challenge because of their high prevalence and antibiotic resistance. As fibrin plays an important role in S. aureus biofilm formation, we hypothesize that coating of the implant surface with fibrinolytic agents can be used as a new method of antibiofilm prophylaxis. The effect of tissue plasminogen activator (tPA) coating on S. aureus biofilm formation was tested with in vitro microplate biofilm assays and an in vivo mouse model of biofilm infection. tPA coating efficiently inhibited biofilm formation by various S. aureus strains. The effect was dependent on plasminogen activation by tPA, leading to subsequent local fibrin cleavage. A tPA coating on implant surfaces prevented both early adhesion and later biomass accumulation. Furthermore, tPA coating increased the susceptibility of biofilm infections to antibiotics. In vivo, significantly fewer bacteria were detected on the surfaces of implants coated with tPA than on control implants from mice treated with cloxacillin. Fibrinolytic coatings (e.g., with tPA) reduce S. aureus biofilm formation both in vitro and in vivo, suggesting a novel way to prevent bacterial biofilm infections of indwelling medical devices.
  •  
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