| 1. |
- Vahasarja, N., et al.
(author)
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Infective Endocarditis Among High-risk Individuals Before and After the Cessation of Antibiotic Prophylaxis in Dentistry: A National Cohort Study
- 2022
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In: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 75:7, s. 1171-1178
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Journal article (peer-reviewed)abstract
- The findings of this cohort study suggest no increased incidence of oral streptococcal infective endocarditis among high-risk individuals in Sweden since the recommended cessation of antibiotic prophylaxis in dentistry for the prevention of endocarditis in October 2012. Background A few years after the publication of the British guidelines, national recommendations were published by the Swedish Medical Products Agency in October 2012, promoting the cessation of antibiotic prophylaxis in dentistry for the prevention of infective endocarditis (IE). The aim of this study was to evaluate whether the incidence of oral streptococcal IE increased among high-risk individuals after October 2012. Methods This nationwide cohort study included all adult individuals (>17 years) living in Sweden from January 2008 to January 2018, with a diagnose code or surgical procedure code indicating high risk of IE. Cox proportional hazard models were performed to calculate adjusted ratios of oral streptococcal IE before and after October 2012 between high-risk individuals and references. Results This study found no increased incidence of oral streptococcal IE among high-risk individuals during the 5 years after the cessation, compared with before. Hazard rate ratios were 15.4 (95% confidence interval [CI]: 8.3-28.5) before and 20.7 (95% CI: 10.0-42.7) after October 2012 for prevalent high-risk individuals. Corresponding ratios for incident high-risk individuals were 66.8 (95% CI: 28.7-155.6) and 44.6 (95% CI: 22.9-86.9). Point estimates for interaction with time period were 1.4 (95% CI: .6-3.5) and 0.8 (95% CI: .5-1.3) for prevalent and incident high-risk individuals, respectively. Conclusion The results suggest that the current Swedish recommendation not to administer antibiotic prophylaxis for the prevention of IE in dentistry has not led to an increased incidence of oral streptococcal IE among high-risk individuals.
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| 2. |
- Torres-Sangiao, E, et al.
(author)
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Quantification of Adaptive Immune Responses Against Protein-Binding Interfaces in the Streptococcal M1 Protein
- 2024
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In: Molecular & Cellular Proteomics. - : Elsevier. - 1535-9476 .- 1535-9484. ; 23:5
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Journal article (peer-reviewed)abstract
- Bacterial or viral antigens can contain subdominant protein regions that elicit weak antibody responses upon vaccination or infection although there is accumulating evidence that antibody responses against subdominant regions can enhance the protective immune response. One proposed mechanism for subdominant protein regions is the binding of host proteins that prevent antibody production against epitopes hidden within the protein binding interfaces. Here, we used affinity purification combined with quantitative mass spectrometry (AP-MS) to examine the level of competition between antigen-specific antibodies and host-pathogen protein interaction networks using the M1 protein from Streptococcus pyogenes as a model system. As most humans have circulating antibodies against the M1 protein, we first used AP-MS to show that the M1 protein interspecies protein network formed with human plasma proteins is largely conserved in naïve mice. Immunizing mice with the M1 protein generated a time-dependent increase of anti-M1 antibodies. AP-MS analysis comparing the composition of the M1-plasma protein network from naïve and immunized mice showed significant enrichment of 292 IgG peptides associated with 56 IgG chains in the immune mice. Despite the significant increase of bound IgGs, the levels of interacting plasma proteins were not significantly reduced in the immune mice. The results indicate that the antigen-specific polyclonal IgG against the M1 protein primarily targets epitopes outside the other plasma protein binding interfaces. In conclusion, this study demonstrates that AP-MS is a promising strategy to determine the relationship between antigen-specific antibodies and host-pathogen interaction networks that could be used to define subdominant protein regions of relevance for vaccine development.
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| 3. |
- Dao Nyesiga, Gillian, et al.
(author)
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Tolerogenic dendritic cells generated in vitro using a novel protocol mimicking mucosal tolerance mechanisms represent a potential therapeutic cell platform for induction of immune tolerance.
- 2023
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In: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
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Journal article (peer-reviewed)abstract
- Dendritic cells (DCs) are mediators between innate and adaptive immunity and vital in initiating and modulating antigen-specific immune responses. The most important site for induction of tolerance is the gut mucosa, where TGF-β, retinoic acid, and aryl hydrocarbon receptors collaborate in DCs to induce a tolerogenic phenotype. To mimic this, a novel combination of compounds – the synthetic aryl hydrocarbon receptor (AhR) agonist IGN-512 together with TGF-β and retinoic acid – was developed to create a platform technology for induction of tolerogenic DCs intended for treatment of several conditions caused by unwanted immune activation. These in vitro-generated cells, designated ItolDCs, are phenotypically characterized by their low expression of co-stimulatory and activating molecules along with high expression of tolerance-associated markers such as ILT3, CD103, and LAP, and a weak pro-inflammatory cytokine profile. When co-cultured with T cells and/or B cells, ItolDC-cultures contain higher frequencies of CD25+Foxp3+ regulatory T cells (Tregs), CD49b+LAG3+ ‘type 1 regulatory (Tr1) T cells, and IL-10-producing B cells and are less T cell stimulatory compared to cultures with matured DCs. Factor VIII (FVIII) and tetanus toxoid (TT) were used as model antigens to study ItolDC antigen-loading. ItolDCs can take up FVIII, process, and present FVIII peptides on HLA-DR. By loading both ItolDCs and mDCs with TT, antigen-specific T cell proliferation was observed. Cryo-preserved ItolDCs showed a stable tolerogenic phenotype that was maintained after stimulation with LPS, CD40L, or a pro-inflammatory cocktail. Moreover, exposure to other immune cells did not negatively impact ItolDCs’ expression of tolerogenic markers. In summary, a novel protocol was developed supporting the generation of a stable population of human DCs in vitro that exhibited a tolerogenic phenotype with an ability to increase proportions of induced regulatory T and B cells in mixed cultures. This protocol has the potential to constitute the base of a tolDC platform for inducing antigen-specific tolerance in disorders caused by undesired antigen-specific immune cell activation.
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| 4. |
- Puthia, Manoj, et al.
(author)
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A dual-action peptide-containing hydrogel targets wound infection and inflammation
- 2020
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 12:524
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Journal article (peer-reviewed)abstract
- There is a clinical need for improved wound treatments that prevent both infection and excessive inflammation. TCP-25, a thrombin-derived peptide, is antibacterial and scavenges pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide, thereby preventing CD14 interaction and Toll-like receptor dimerization, leading to reduced downstream immune activation. Here, we describe the development of a hydrogel formulation that was functionalized with TCP-25 to target bacteria and associated PAMP-induced inflammation. In vitro studies determined the polymer prerequisites for such TCP-25-mediated dual action, favoring the use of noncharged hydrophilic hydrogels, which enabled peptide conformational changes and LPS binding. The TCP-25-functionalized hydrogels killed Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa bacteria in vitro, as well as in experimental mouse models of subcutaneous infection. The TCP-25 hydrogel also mediated reduction of LPS-induced local inflammatory responses, as demonstrated by analysis of local cytokine production and in vivo bioimaging using nuclear factor κB (NF-κB) reporter mice. In porcine partial thickness wound models, TCP-25 prevented infection with S. aureus and reduced concentrations of proinflammatory cytokines. Proteolytic fragmentation of TCP-25 in vitro yielded a series of bioactive TCP fragments that were identical or similar to those present in wounds in vivo. Together, the results demonstrate the therapeutic potential of TCP-25 hydrogel, a wound treatment based on the body's peptide defense, for prevention of both bacterial infection and the accompanying inflammation.
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| 5. |
- Bengtsson, Torbjörn, 1955-, et al.
(author)
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The lantibiotic gallidermin acts bactericidal against Staphylococcus epidermidis and Staphylococcus aureus and antagonizes the bacteria-induced proinflammatory responses in dermal fibroblasts
- 2018
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In: MicrobiologyOpen. - : John Wiley & Sons. - 2045-8827. ; 7:6
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Journal article (peer-reviewed)abstract
- Antimicrobial resistance needs to be tackled from new angles, and antimicrobial peptides could be future candidates for combating bacterial infections. This study aims to investigate in vitro the bactericidal effects of the lantibiotic gallidermin on Staphylococcus epidermidis and Staphylococcus aureus, possible cytotoxic effects and its impact on host-microbe interactions. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of gallidermin were determined, and cytotoxicity and proinflammatory effects of gallidermin on fibroblasts, red blood cells (RBCs) and in whole blood were investigated. Both MIC and MBC for all four tested strains of S. epidermidis was 6.25 μg/ml. Both MIC and MBC for methicillin-sensitive S. aureus was 12.5 μg/ml and for methicillin-resistant S. aureus (MRSA) 1.56 μg/ml. Gallidermin displayed no cytotoxic effects on fibroblasts, only a high dose of gallidermin induced low levels of CXCL8 and interleukin-6. Gallidermin hemolyzed less than 1% of human RBCs, and did not induce reactive oxygen species production or cell aggregation in whole blood. In cell culture, gallidermin inhibited the cytotoxic effects of the bacteria and totally suppressed the bacteria-induced release of CXCL8 and interleukin-6 from fibroblasts. We demonstrate that gallidermin, expressing low cell cytotoxicity, is a promising candidate for treating bacterial infections caused by S. epidermidis and S. aureus, especially MRSA.
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| 6. |
- Movert, Elin, et al.
(author)
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Streptococcal M protein promotes IL-10 production by cGAS-independent activation of the STING signaling pathway
- 2018
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In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7374 .- 1553-7366. ; 14:3
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Journal article (peer-reviewed)abstract
- From an evolutionary point of view a pathogen might benefit from regulating the inflammatory response, both in order to facilitate establishment of colonization and to avoid life-threatening host manifestations, such as septic shock. In agreement with this notion Streptococcus pyogenes exploits type I IFN-signaling to limit detrimental inflammation in infected mice, but the host-pathogen interactions and mechanisms responsible for induction of the type I IFN response have remained unknown. Here we used a macrophage infection model and report that S. pyogenes induces anti-inflammatory IL-10 in an M protein-dependent manner, a function that was mapped to the B- and C-repeat regions of the M5 protein. Intriguingly, IL-10 was produced downstream of type I IFN-signaling, and production of type I IFN occurred via M protein-dependent activation of the STING signaling pathway. Activation of STING was independent of the cytosolic double stranded DNA sensor cGAS, and infection did not induce detectable release into the cytosol of either mitochondrial, nuclear or bacterial DNA–indicating DNA-independent activation of the STING pathway in S. pyogenes infected macrophages. These findings provide mechanistic insight concerning how S. pyogenes induces the type I IFN response and identify a previously unrecognized macrophage-modulating role for the streptococcal M protein that may contribute to curb the inflammatory response to infection.
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| 7. |
- Axelsson, Malin, 1964, et al.
(author)
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The significance of asthma follow-up consultations for adherence to asthma medication, asthma medication beliefs and asthma control
- 2015
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In: Nursing Research and Practice. - : Hindawi Limited. - 2090-1429 .- 2090-1437. ; 2015
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Journal article (peer-reviewed)abstract
- Objective. The aim was to investigate adherence to asthma medication treatment, medication beliefs, and asthma control in relation to asthma follow-up consultations in asthmatics in the general population. A further aim was to describe associations between adherence, medication beliefs, and asthma control.Method. In the population-based West Sweden Asthma Study, data allowing calculation of adherence for 4.5 years based on pharmacy records were obtained from 165 adult asthmatics. Additional data were collected through questionnaires and structured interviews.Results. The mean adherence value for filled prescriptions for regular asthma medication was 68% (median 55.3%) but varied over the year under study. Adherence to combination inhalers with corticosteroids and long-acting beta2agonists was higher than adherence to single inhalers with corticosteroids only. More than one-third of participants reported not having seen an asthma nurse or physician for several years. Regular asthma follow-up consultations were associated with both higher adherence and the belief that asthma medication was necessary but were not associated with asthma control.Conclusions. Adherence to asthma medication treatment was low and varied over the year under study. The current study suggests that quality improvements in asthma care are needed if adherence to asthma medication is to be improved.
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| 8. |
- Ketelhuth, D. F., et al.
(author)
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Identification of a danger-associated peptide from apolipoprotein B100 (ApoBDS-1) that triggers innate proatherogenic responses
- 2011
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In: Circulation. - Stockholm : Karolinska Institutet, Dept of Medicine, Solna. - 1524-4539 .- 0009-7322. ; 124:22
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Journal article (peer-reviewed)abstract
- BACKGROUND: Subendothelial deposited low-density lipoprotein particles are a known inflammatory factor in atherosclerosis. However, the causal components derived from low-density lipoprotein are still poorly defined. Apolipoprotein B100 (ApoB100) is the unexchangeable protein component of low-density lipoprotein, and the progression of atherosclerosis is associated with immune responses to ApoB100-derived peptides. In this study, we analyzed the proinflammatory activity of ApoB100 peptides in atherosclerosis. METHODS AND RESULTS: By screening a peptide library of ApoB100, we identified a distinct native peptide referred to as ApoB100 danger-associated signal 1 (ApoBDS-1), which shows sequence-specific bioactivity in stimulation of interleukin-8, CCL2, and interleukin-6. ApoBDS-1 activates mitogen-activated protein kinase and calcium signaling, thereby effecting the expression of interleukin-8 in innate immune cells. Ex vivo stimulation of carotid plaques with ApoBDS-1 enhances interleukin-8 and prostaglandin E release. Furthermore, we demonstrated that ApoBDS-1-positive peptide fragments are present in atherosclerotic lesions using immunoassays and that low-molecular-weight fractions isolated from plaque show ApoBDS-1 activity inducing interleukin-8 production. CONCLUSIONS: Our data show that ApoBDS-1 is a previously unrecognized peptide with robust proinflammatory activity, contributing to the disease-promoting effects of low-density lipoprotein in the pathogenesis of atherosclerosis.
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| 9. |
- Grant, Melissa, et al.
(author)
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The Human Salivary Antimicrobial Peptide Profile according to the Oral Microbiota in Health, Periodontitis and Smoking.
- 2019
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In: Journal of Innate Immunity. - : S. Karger. - 1662-811X .- 1662-8128. ; 11:5, s. 432-443
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Journal article (peer-reviewed)abstract
- Antimicrobial peptides (AMPs) are a diverse family of peptides that defend the mucosal surfaces of the oral cavity and other locations. Many AMPs have multiple functions and properties that influence aspects of innate defense and colonization by microorganisms. The human oral cavity is home to the second-most diverse microbiome, and the health of the mouth is influenced by the presence of these bacteria as well as by extrinsic factors such as periodontitis and smoking. This study hypothesized that the AMP profile is different in the presence of extrinsic factors and that this would also be reflected in the bacteria present. The AMP profile was analyzed by quantitative selected-reaction-monitoring mass spectrometry analysis and 40 bacterial species were quantified by DNA-DNA hybridization in saliva donated by 41 individuals. Periodontal status was assessed through dental examination and smoking status through medical charting. Periodontal health (in nonsmokers) was associated with a higher abundance of ribonuclease 7, protachykinin 1, β-defensin 128, lipocalin 1, bactericidal permeability-increasing protein fold-containing family B member 3, and bone-marrow proteoglycan. Nonsmoking periodontal disease was associated with an abundance of neutrophil defensin 1 and cathelicidin. However, 7 AMPs were overabundant in periodontal disease in smokers: adrenomedullin, eosinophil peroxidase, 3 different histones, myeloperoxidase, and neutrophil defensin 1. There were no differentially abundant AMPs in smokers versus nonsmokers with periodontal health. Correlation network inference of healthy nonsmokers, healthy smokers, nonsmoking periodontitis, or smoking periodontitis donors demonstrated very different networks growing in complexity with increasing numbers of stressors. The study highlights the importance of the interaction between the oral cavity and its resident microbiota and how this may be influenced by periodontal disease and smoking.
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| 10. |
- Larsson, Åke, et al.
(author)
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Immunohistochemistry of the B-cell Component in Lower Lip Salivary Glands of Sjögren's Syndrome and Healthy Subjects
- 2005
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In: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 61:1, s. 98-107
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Journal article (other academic/artistic)abstract
- Serial sections of lower lip salivary gland (LSG) biopsies were examined by immunohistochemistry, using a battery of B- and partly T-related antibodies (CD5, CD20, CD21, CD27, CD38, CD45RO, CD79a, Bcl-2 and Bcl-6) in different groups of subjects: healthy controls and clinically verified smoking or nonsmoking cases of primary Sjögren's syndrome (SS). The purpose was to characterize the B-cell pattern of the lymphocytic foci and of the tiny perivascular infiltrates preceding the development of foci. Hyperplastic tonsil was used as stain control. In normal LSG, widely dispersed CD38+ and CD79a+ as well as some CD5+ cells are a normal constituent, with lack of staining with the other antibodies. In SS/LSG, the lymphocytic foci showed staining with all the antibodies, with variable degrees of overlapping or nonoverlapping. In SS/LSG of nonsmokers, CD20+ B cells make up a prominent part of the fully developed periductal lymphocytic foci, not overlapping with CD45RO. Also, CD20+ B cells did not overlap in the infiltrates with colocalized CD27+/CD38+ cells. CD20+ B cells and CD45RO+ T cells also occur as minute infiltrates perivascularly in areas of no foci in SS/LSG as well as in SS smokers lacking the typical foci. Smokers lack foci, but tiny infiltrates express CD20 as well CD45R0. Our findings suggest that CD20+ B cells and CD45RO+ T cells are early immigrants in the LSG of SS of smokers as well as nonsmokers and that another subgroup of CD27+/CD38+ B cells gradually mix with the first two to form the characteristic foci in SS/LSG. The simultaneous demonstration of CD20+ and CD27+ B cells in SS/LSG may constitute a significant diagnostic tool. Further, the findings suggest that the early immigrating lymphocytes may have been primed at a site remote from the glands before arriving via the blood to the gland tissue.
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