| 1. |
- Jarneborn, Anders, et al.
(author)
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Tofacitinib treatment aggravates Staphylococcus aureus septic arthritis, but attenuates sepsis and enterotoxin induced shock in mice
- 2020
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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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.
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| 2. |
- Mohammad, Majd, et al.
(author)
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The role of Staphylococcus aureus lipoproteins in hematogenous septic arthritis.
- 2020
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10
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Journal article (peer-reviewed)abstract
- Permanent joint dysfunction is a devastating complication in patients with septic arthritis. Staphylococcus aureus (S. aureus) lipoproteins (Lpp), the predominant ligands for TLR2, are known to be arthritogenic and induce bone destruction when introduced directly into the joint. Here, we aim to investigate the importance of S. aureus Lpp and TLR2 in a hematogenous septic arthritis model, which is the most common route of infection in humans. C57BL/6 wild-type and TLR2 deficient mice were intravenously inoculated with S. aureus Newman parental strain or its lipoprotein-deficient Δlgt mutant strain. The clinical course of septic arthritis, radiological changes, and serum levels of cytokines and chemokines, were assessed. Newman strain induced more severe and frequent clinical septic polyarthritis compared to its Δlgt mutant in TLR2 deficient mice, but not in wild-type controls. Bone destruction, however, did not differ between groups. Lpp expression was associated with higher mortality, weight loss as well as impaired bacterial clearance in mouse kidneys independent of TLR2. Furthermore, Lpp expression induced increased systemic pro-inflammatory cytokine and neutrophil chemokine release. Staphylococcal Lpp are potent virulence factors in S. aureus systemic infection independent of host TLR2 signalling. However, they have a limited impact on bone erosion in hematogenous staphylococcal septic arthritis.
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| 3. |
- Na, Manli, et al.
(author)
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The Expression of von Willebrand Factor-Binding Protein Determines Joint-Invading Capacity of Staphylococcus aureus, a Core Mechanism of Septic Arthritis.
- 2020
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In: mBio. - 2150-7511. ; 11:6
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Journal article (peer-reviewed)abstract
- Septic arthritis, one of the most dangerous joint diseases, is predominantly caused by Staphylococcus aureus In contrast, coagulase-negative staphylococci are rarely found in septic arthritis. We hypothesize that coagulases released by S. aureus, including coagulase (Coa) and von Willebrand factor-binding protein (vWbp), play potent roles in the induction of septic arthritis. Four isogenic S. aureus strains differing in expression of coagulases (wild-type [WT] Newman, Δcoa, Δvwb, and Δcoa Δvwb) were used to induce septic arthritis in both wild-type and von Willebrand factor (vWF)-deficient mice. Septic arthritis severity was greatly reduced when wild-type mice were infected with the Δcoa Δvwb and Δvwb variants compared to WT or Δcoa strains, suggesting that vWbp rather than Coa is a major virulence factor in S. aureus septic arthritis. vWF-deficient mice were more susceptible to bone damage in septic arthritis, especially when the Δvwb strain was used. Importantly, no difference in arthritis severity between the Δvwb and WT strains was observed in vWF-deficient mice. Collectively, we conclude that vWbp production by S. aureus enhances staphylococcal septic arthritis.IMPORTANCE Septic arthritis remains one of the most dangerous joint diseases with a rapidly progressive disease character. Despite advances in the use of antibiotics, permanent reductions in joint function due to joint deformation and deleterious contractures occur in up to 50% of patients with septic arthritis. So far, it is still largely unknown how S. aureus initiates and establishes joint infection. Here, we demonstrate that von Willebrand factor-binding protein expressed by S. aureus facilitates the initiation of septic arthritis. Such effect might be mediated through its interaction with a host factor (von Willebrand factor). Our finding contributes significantly to the full understanding of septic arthritis etiology and will pave the way for new therapeutic modalities for this devastating disease.
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