| 1. |
- Ali, Abukar, 1988, et al.
(author)
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Antibiotic-killed Staphylococcus aureus induces destructive arthritis in mice.
- 2015
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In: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 67:1, s. 107-116
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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
(author)
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Biologics in Staphylococcus aureus arthritis
- 2016
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Doctoral thesis (other academic/artistic)abstract
- The emergence of new type of drugs known as biologics has led to rapid disease improvements in many autoimmune arthritic patients. Nevertheless, most of these biologics are immunomodulators that may consequently increase the susceptibility of patients towards infections, such as septic arthritis. Septic arthritis is still considered a major public health challenge due to its rapidly progressive disease character with poor prognosis regarding joint functions. It is mainly caused by Staphylococcus aureus and despite optimal antibiotic treatment, nearly half of patients have permanent joint dysfunction. The main aim of this thesis was to investigate the inflammatory response of the host to living as well as antibiotics-killed S. aureus and to study the effect of biologics on the course of staphylococcal infections. The role of host inflammatory response on post-infectious joint dysfunction using antibiotic-killed S. aureus was the subject of Paper I of this thesis. The main focus of Paper II and III were to study the effects of different biologics treatments on S. aureus induced septic arthritis and sepsis. We demonstrated that antibiotic-killed S. aureus is capable of inducing and maintaining destructive arthritis. By using different knockout mice, we showed that this type of arthritis was mediated through TLR-2, TNFR1 and RAGE receptors. Furthermore, we found that insoluble cell debris was a key initiator of this type of arthritis. Finally, anti-TNF therapy attenuated the arthritis caused by antibiotic-killed S. aureus. All the biologic treatments tested (including anti-TNF therapy, CTLA4-Ig and IL-1 Ra) aggravated S. aureus infections but had different clinical manifestations. Both CTLA4-Ig and IL-1 Ra therapy significantly increased the susceptibility to S. aureus induced septic arthritis in mice. Anti-TNF therapy on the other hand resulted in more severe weight loss and impaired the bacterial clearance ability of the host. In conclusion, antibiotic-killed S. aureus induced chronic destructive arthritis and anti-TNF therapy attenuated this type of joint inflammation. In the living S. aureus induced septic arthritis, all tested biologics complicated the disease course. Therefore, the potential dangers associated with biologics should be taken into account and patients with high risk of S. aureus bacteremia might be considered to refrain from them.
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| 3. |
- Ali, Abukar, 1988, et al.
(author)
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CTLA4-Ig but not anti-TNF therapy promotes staphylococcal septic arthritis in mice.
- 2015
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 212:8, s. 1308-1316
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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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| 4. |
- Ali, Abukar, 1988, et al.
(author)
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IL-1 Receptor Antagonist Treatment Aggravates Staphylococcal Septic Arthritis and Sepsis in Mice.
- 2015
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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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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| 5. |
- Bergmann, Berglind, et al.
(author)
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Pre-treatment with IL2 gene therapy alleviates Staphylococcus aureus arthritis in mice.
- 2020
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In: BMC infectious diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 20:1
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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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| 6. |
- Boldock, Emma, et al.
(author)
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Human skin commensals augment Staphylococcus aureus pathogenesis.
- 2018
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In: Nature microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 3:8, s. 881-90
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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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| 7. |
- Fatima, Farah, et al.
(author)
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Radiological features of experimental staphylococcal septic arthritis by micro computed tomography scan.
- 2017
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 12:2
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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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| 8. |
- Fei, Ying, et al.
(author)
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Commensal Bacteria Augment Staphylococcus aureus septic Arthritis in a Dose-Dependent Manner.
- 2022
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In: Frontiers in cellular and infection microbiology. - : Frontiers Media SA. - 2235-2988. ; 12
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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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| 9. |
- Hu, Zhicheng, et al.
(author)
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The impact of aging and TLR2 deficiency on the clinical outcomes of Staphylococcus aureus bacteremia.
- 2023
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 228:3, s. 332-342
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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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| 10. |
- 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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