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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.

Phenol-soluble modulin α and β display divergent roles in staphylococcal infection and its associated septic arthritis - whereas PSMα is a virulence factor for neutrophils that worsens infection, PSMβ protects from the development of septic arthritis.

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.

Mohammad et al. show that subcutaneous injection of Staphylococcus aureus lipoproteins (Lpp) leads to the infiltration of neutrophils and monocytes/macrophages, inducing skin lesions in mice. They find that S. aureus Lpp promotes abscess formation, which protects bacteria from innate immune killing, suggesting an intriguing bacterial immune evasion mechanism.

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. [ABSTRACT FROM AUTHOR]

Septic arthritis, most often caused by Staphylococcus aureus, is a rapidly progressive and destructive joint disease with substantial mortality and morbidity. Staphylococcus aureus lipoproteins (Lpps) are known to induce arthritis and bone destruction. Here, we aimed to investigate the bone resorptive effect of S. aureus Lpps in a murine arthritis model by intra-articular injection of purified S. aureus Lpps, synthetic lipopeptides, and live S. aureus strains. Analyses of the bone mineral density (BMD) of the distal femur bone were performed. Intra-articular injection of both live S. aureus and purified S. aureus Lpps were shown to significantly decrease total- and trabecular BMD. Liquid chromatography–mass spectrometry analyses revealed that the Lpps expressed by S. aureus SA113 strain contain both diacyl and triacyl lipid moieties. Interestingly, synthetic diacylated lipopeptide, Pam2CSK4, was more potent in inducing bone resorption than synthetic triacylated lipopeptide, Pam3CSK4. Modified lipoproteins lacking the lipid moiety were deprived of their bone resorptive abilities. Monocyte depletion by clodronate liposomes fully abrogated the bone resorptive capacity of S. aureus lipoproteins. Our data suggest that S. aureus Lpps induce bone resorption in locally-induced murine arthritis, an effect mediated by their lipid-moiety through monocytes/macrophages.

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.

Rapid bone destruction often leads to permanent joint dysfunction in patients with septic arthritis, which is mainly caused by Staphylococcus aureus (S. aureus). Staphylococcal cell wall components are known to induce joint inflammation and bone destruction. Here, we show that a single intra-articular injection of S. aureus lipoproteins (Lpps) into mouse knee joints induced chronic destructive macroscopic arthritis through TLR2. Arthritis was characterized by rapid infiltration of neutrophils and monocytes. The arthritogenic effect was mediated mainly by macrophages/monocytes and partially via TNF-α but not by neutrophils. Surprisingly, a S. aureus mutant lacking Lpp diacylglyceryl transferase (lgt) caused more severe joint inflammation, which coincided with higher bacterial loads of the lgt mutant in local joints than those of its parental strain. Coinjection of pathogenic S. aureus LS-1 with staphylococcal Lpps into mouse knee joints caused improved bacterial elimination and diminished bone erosion. The protective effect of the Lpps was mediated by their lipid moiety and was fully dependent on TLR2 and neutrophils. The blocking of CXCR2 on neutrophils resulted in total abrogation of the protective effect of the Lpps. Our data demonstrate that S. aureus Lpps elicit innate immune responses, resulting in a double-edged effect. On the one hand, staphylococcal Lpps boost septic arthritis. On the other hand, Lpps act as adjuvants and activate innate immunity, which could be useful for combating infections with multiple drug-resistant strains.

Staphylococcus aureus (S. aureus) causes a broad range of infections. Toll-like receptor (TLR) 2 senses the S. aureus lipoproteins in S. aureus infections. Aging raises the risk of infection. Our aim was to understand how aging and TLR2 affect 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 for increased mortality rates 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 rates without relying on TLR2. In vitro, both aging and TLR2 deficiency down-regulated 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Tofacitinib, a Janus kinase inhibitor, is a novel immunosuppressive drug for treatment of rheumatoid arthritis. 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 pretreated with tofacitinib were intranasally infected with a clinical strain of HSV-1 and monitored for infection severity and antiviral 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 herpes simplex encephalitis in mice, by impairing antiviral response induced by monocytes and microglia. [ABSTRACT FROM AUTHOR]

Despite being a major bacterial factor in alerting the human immune system, the role of Staphylococcus aureus (S. aureus) lipoproteins (Lpp) in skin infections remains largely unknown. Here, we demonstrated that subcutaneous injection of S. aureus Lpp led to infiltration of neutrophils and monocytes/macrophages and induced skin lesions in mice. Lipid-moiety of S. aureus Lpp and host TLR2 was responsible for such effect. Lpp-deficient S. aureus strains exhibited smaller lesion size and reduced bacterial loads than their parental strains; the altered phenotype in bacterial loads was TLR2-independent. Lpp expression in skin infections contributed to imbalanced local hemostasis toward hypercoagulable state. Depletion of leukocytes or fibrinogen abrogated the effects induced by Lpp in terms of skin lesions and bacterial burden. Our data suggest that S. aureus Lpp induce skin inflammation and promote abscess formation that protects bacteria from innate immune killing. This suggests an intriguing bacterial immune evasion mechanism. Mohammad et al. show that subcutaneous injection of Staphylococcus aureus lipoproteins (Lpp) leads to the infiltration of neutrophils and monocytes/macrophages, inducing skin lesions in mice. They find that S. aureus Lpp promotes abscess formation, which protects bacteria from innate immune killing, suggesting an intriguing bacterial immune evasion mechanism. [ABSTRACT FROM AUTHOR]

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., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of FEMS.)

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, Δ coa , Δ vwb , and Δ coa Δ vwb ) 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 Δ coa Δ vwb and Δ vwb variants compared to WT or Δ coa 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 Δ vwb strain was used. Importantly, no difference in arthritis severity between the Δ vwb 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., (Copyright © 2020 Na et al.)

The complement system plays an essential role in the innate immune response and protection against bacterial infections. However, detailed knowledge regarding the role of complement in Staphylococcus aureus septic arthritis is still largely missing. In this study, we elucidated the roles of selected complement proteins in S. aureus septic arthritis. Mice lacking the complement component 3 (C3(-/-)), complement factor B (fB(-/-)), and receptor for C3-derived anaphylatoxin C3a (C3aR(-/-)) and wild-type (WT) control mice were intravenously or intra-articularly inoculated with S. aureus strain Newman. The clinical course of septic arthritis, as well as histopathological and radiological changes in joints, was assessed. After intravenous inoculation, arthritis severity and frequency were significantly higher in C3(-/-)mice than in WT controls, whereas fB(-/-)mice displayed intermediate arthritis severity and frequency. This was in accordance with both histopathological and radiological findings. C3, but not fB, deficiency was associated with greater weight loss, more frequent kidney abscesses, and higher bacterial burden in kidneys. S. aureus opsonized with C3(-/-)sera displayed decreased uptake by mouse peritoneal macrophages compared with bacteria opsonized with WT or fB(-/-)sera. C3aR deficiency had no effect on the course of hematogenous S. aureus septic arthritis. We conclude that C3 deficiency increases susceptibility to hematogenous S. aureus septic arthritis and impairs host bacterial clearance, conceivably due to diminished opsonization and phagocytosis of S. aureus., (Copyright © 2016 Na et al.)

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., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Patient care models have been implemented and documented worldwide. Many studies have focused on features that hinder and facilitate the shift to such models, including the implementation process, staff involvement, resistance to new models and cultural dimensions. However, few studies have identified the potential effects of such new care models from a patient perspective. The aim of the present study was to investigate whether patients did in fact perceive the intentions of partnership in the new care model 1 year after its implementation., Methods: Sixteen participants were interviewed, selected from two wards in a medical department where a new care model had been implemented 1 year earlier. A directed deductive content analysis was selected. The aim of the directed approach to content analysis was to investigate to what extent the new care model had been implemented, using patients' perspectives to describe the level of implementation. A coding framework was developed based on a theoretical paper that described the key features of the new care model., Results: The implementation of person-centred care had clearly occurred to a large degree, even if some patients appeared not to have been exposed to the model at all. Aspects of the newly implemented care model were obvious; however, it was also clear that implementation was not complete. The analysis showed that patients felt listened to and that their own perception of the situation had been noted. Patients spontaneously expressed that they felt that the staff saw them as persons and did not solely focus on their disease. It was also stated that not every ailment or aspect of a patient's illness needed to be addressed or resolved for open listening to be perceived as a positive experience., Conclusions: The findings indicate that even though some patients were not interested in participating and playing an active role in their own care, this might relate to a lack of understanding on how to invite them to do so and to increase their confidence. To change healthcare from a paternalistic system to care where patients are seen as partners may require pedagogical skills.