| 1. |
- Movert, Elin, et al.
(författare)
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Interplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Variability in disease severity caused by a microbial pathogen is impacted by each infection representing a unique combination of host and pathogen genomes. Here, we show that the outcome of invasive Streptococcus pyogenes infection is regulated by an interplay between human STING genotype and bacterial NADase activity. S. pyogenes-derived c-di-AMP diffuses via streptolysin O pores into macrophages where it activates STING and the ensuing type I IFN response. However, the enzymatic activity of the NADase variants expressed by invasive strains suppresses STING-mediated type I IFN production. Analysis of patients with necrotizing S. pyogenes soft tissue infection indicates that a STING genotype associated with reduced c-di-AMP-binding capacity combined with high bacterial NADase activity promotes a ‘perfect storm’ manifested in poor outcome, whereas proficient and uninhibited STING-mediated type I IFN production correlates with protection against host-detrimental inflammation. These results reveal an immune-regulating function for bacterial NADase and provide insight regarding the host-pathogen genotype interplay underlying invasive infection and interindividual disease variability.
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| 2. |
- Neumann, Ariane, et al.
(författare)
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Immunoregulation of Neutrophil Extracellular Trap Formation by Endothelial-Derived p33 (gC1q Receptor)
- 2018
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 10:1, s. 30-43
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Tidskriftsartikel (refereegranskat)abstract
- The formation of neutrophil extracellular traps (NETs) is a host defence mechanism, known to facilitate the entrapment and growth inhibition of many bacterial pathogens. It has been implicated that the translocation of myeloperoxidase (MPO) from neutrophilic granules to the nucleus is crucial to this process. Under disease conditions, however, excessive NET formation can trigger self-destructive complications by releasing pathologic levels of danger-associated molecular pattern molecules (DAMPs). To counteract such devastating immune reactions, the host has to rely on precautions that help circumvent these deleterious effects. Though the induction of DAMP responses has been intensively studied, the mechanisms that are used by the host to down-regulate them are still not understood. In this study, we show that p33 is an endothelial-derived protein that has the ability to annul NET formation. We found that the expression of human p33 is up-regulated in endothelial cells upon infections with Streptococcus pyogenes bacteria. Using tissue biopsies from a patient with streptococcal necrotising fasciitis, we monitored co-localisation of p33 with MPO. Further in vitro studies revealed that p33 is able to block the formation of DAMP-induced NET formation by inhibiting the enzymatic activity of MPO. Additionally, mice challenged with S. pyogenes bacteria demonstrated diminished MPO activity when treated with p33. Together, our results demonstrate that host-derived p33 has an important immunomodulating function that helps to counterbalance an overwhelming DAMP response.
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| 3. |
- Oscarsson, Nicklas, 1974, et al.
(författare)
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Radiation-induced cystitis treated with hyperbaric oxygen therapy (RICH-ART): a randomised, controlled, phase 2–3 trial
- 2019
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 20:11, s. 1602-1614
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 Elsevier Ltd Background: Late radiation cystitis is an adverse effect of cancer treatment with radiotherapy in the pelvic region. Symptoms of late radiation cystitis can be assessed with the Expanded Prostate Index Composite Score (EPIC). Previous reports indicate that hyperbaric oxygen therapy reduces symptoms from late radiation cystitis, but the evidence is predominantly based on non-randomised and retrospective studies. We aimed to assess whether hyperbaric oxygen therapy would mitigate symptoms of late radiation cystitis. Methods: We did a randomised, controlled, phase 2–3 trial (RICH-ART [Radiation Induced Cystitis treated with Hyperbaric oxygen—A Randomised controlled Trial]) at five Nordic university hospitals. All patients aged 18–80 years, with pelvic radiotherapy completed at least 6 months previously, a score of less than 80 in the urinary domain of the Expanded Prostate Index Composite Score (EPIC), and referred to participating hyperbaric clinics due to symptoms of late radiation cystitis, were eligible for inclusion. Exclusion criteria were ongoing bleeding requiring blood transfusion exceeding 500 mL in the past 4 weeks, permanent urinary catheter, bladder capacity less than 100 mL, fistula in the urinary bladder, previous treatment with hyperbaric oxygen therapy for late radiation injuries, and contraindications to hyperbaric oxygen therapy. After computer-generated 1:1 randomisation with block sizes of four for each stratification group (sex, time from radiotherapy to inclusion, and previous invasive surgery in the pelvic area), patients received hyperbaric oxygen therapy (30–40 sessions, 100% oxygen, breathed at a pressure of 240–250 kPa, for 80–90 min daily) or standard care with no restrictions for other medications or interventions. No masking was applied. The primary outcome was change in patient-perceived urinary symptoms assessed with EPIC from inclusion to follow-up at visit 4 (6–8 months later), measured as absolute change in EPIC urinary total score. RICH-ART closed enrolment on Dec 31, 2017; the last follow-up data will be compiled in 2023. RICH-ART is registered with ClinicalTrials.gov, number NCT01659723, and with the European Medicines Agency, number EudraCT 2012-001381-15. Findings: Of 223 patients screened between May 9, 2012, and Dec 20, 2017, 87 patients were enrolled and randomly assigned to either hyperbaric oxygen therapy (n=42) or standard care (n=45). After excluding eight patients who withdrew consent directly after randomisation (one in the hyperbaric oxygen therapy group and seven in the standard care group), 79 were included in the intention-to-treat analyses (n=41 in the hyperbaric oxygen therapy group, n=38 in the standard care group). Median time from randomisation to visit 4 was 234 days (IQR 210–262) in the hyperbaric oxygen therapy group and 217 days (195–237) in the standard care group. The difference between change in group mean of EPIC urinary total score at visit 4 was 10·1 points (95% CI 2·2–18·1; p=0·013; 17·8 points [SD 18·4] in the hyperbaric oxygen therapy group vs 7·7 points [15·5] in the standard care group). 17 (41%) of 41 patients in the hyperbaric oxygen therapy group experienced transient grade 1–2 adverse events, related to sight and hearing, during the period of hyperbaric oxygen therapy. Interpretation: Our results suggest that hyperbaric oxygen therapy relieves symptoms of late radiation cystitis. We conclude that hyperbaric oxygen therapy is a safe and well tolerated treatment. Funding: The regional research fund of Region Västra Götaland, Sweden, the regional Health Technology Assessment Centre at Sahlgrenska University Hospital, Sweden, and Lions Cancer Research Fund of Western Sweden.
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| 4. |
- Westman, Johannes, et al.
(författare)
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Protein SIC secreted from Streptococcus pyogenes forms complexes with extracellular histones that boost cytokine production
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9:FEB, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Innate immunity relies on an effective recognition of the pathogenic microorganism as well as on endogenous danger signals. While bacteria in concert with their secreted virulence factors can cause a number of inflammatory reactions, danger signals released at the site of infection may in addition determine the amplitude of such responses and influence the outcome of the disease. Here, we report that protein SIC, Streptococcal Inhibitor of Complement, an abundant secreted protein from Streptococcus pyogenes, binds to extracellular histones, a group of danger signals released during necrotizing tissue damage. This interaction leads to the formation of large aggregates in vitro. Extracellular histones and SIC are abundantly expressed and seen colocalized in biopsies from patients with necrotizing soft-tissue infections caused by S. pyogenes. In addition, binding of SIC to histones neutralized their antimicrobial activity. Likewise, the ability of histones to induce hemolysis was inhibited in the presence of SIC. However, when added to whole blood, SIC was not able to block the pro-inflammatory effect of histones. Instead SIC boosted the histone-triggered release of a broad range of cytokines and chemokines, including IL-6, TNF-α, IL-8, IL-1β, IL-1ra, G-CSF, and IFN-γ. These results demonstrate that the interaction between SIC and histones has multiple effects on the host response to S. pyogenes infection.
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| 5. |
- Ånell, Rickard, 1971-
(författare)
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Decompression strain during long-duration, high-altitude exposures : Effects of intermittent excursions to moderate altitude and inspired fractions of oxygen
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Today´s tactical demands and new technical solutions in fighter aircraft entail longer exposure periods at higher altitudes than before. A low cabin pressure protects pilots from pulmonary barotrauma in case of a sudden loss of cabin pressure, however it can also generate a supersaturation of nitrogen (N2) in the tissues, increasing the risks of bubble formation and decompression sickness (DCS). To be able to perform long-duration missions at high altitude, in-air refuelling is required, often performed at lower cabin altitudes between 15000-20000 ft. Therefore, the aim of the thesis was to explore different mechanisms that could affect decompressive strain during long and intermittent high altitude-exposures. In our experiments, upon which this thesis is based, we examined how ambient pressure and different breathing gas-mixtures affected the N2 washout and presence of venous gas emboli (VGE) as markers of decompressive strain, in particular during long-duration exposures. The thesis is based on four different studies and a short communication. The first two studies measured N2-washout during normoxic exposures. In studies I- IV, VGE were measured during normoxic or hyperoxic conditions with different ambient pressures. The results show that a high enough pressure increase compressed the existing bubbles and decreased the number of VGE before returning to high altitude. Hyperoxia alone did not protect subjects from VGE formation and DCS, whereas a combination of an early recompression during high-altitude exposures while breathing 100% O2 decreased VGE, probably by changing the bubble content from N2 to O2, making the bubbles unstable, probably reducing the risk for DCS returning to high altitude.
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