| 1. |
- van Sorge, Nina M., et al.
(author)
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Bacterial protein domains with a novel Ig-like fold target human CEACAM receptors
- 2021
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In: EMBO Journal. - : Wiley-VCH Verlagsgesellschaft. - 0261-4189 .- 1460-2075. ; 40
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Journal article (peer-reviewed)abstract
- Streptococcus agalactiae, also known as group B Streptococcus (GBS), is the major cause of neonatal sepsis in humans. A critical step to infection is adhesion of bacteria to epithelial surfaces. GBS adhesins have been identified to bind extracellular matrix components and cellular receptors. However, several putative adhesins have no host binding partner characterised. We report here that surface-expressed β protein of GBS binds to human CEACAM1 and CEACAM5 receptors. A crystal structure of the complex showed that an IgSF domain in β represents a novel Ig-fold subtype called IgI3, in which unique features allow binding to CEACAM1. Bioinformatic assessment revealed that this newly identified IgI3 fold is not exclusively present in GBS but is predicted to be present in adhesins from other clinically important human pathogens. In agreement with this prediction, we found that CEACAM1 binds to an IgI3 domain found in an adhesin from a different streptococcal species. Overall, our results indicate that the IgI3 fold could provide a broadly applied mechanism for bacteria to target CEACAMs.
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| 2. |
- Bergman Bruhn, Åsa, et al.
(author)
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Motivational factors for occupational safety and health improvements : A mixed-method study within the Swedish equine sector
- 2023
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In: Safety Science. - : Elsevier. - 0925-7535 .- 1879-1042. ; 159
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Journal article (peer-reviewed)abstract
- A well-functioning systematic occupational safety and health management is beneficial for both individuals and organizations, and employee motivation seems to be crucial for positive outcomes. Occupational safety and health issues are a major concern for the Swedish equine sector since the work environment in horse stables is known to be characterized by low mechanization, high physical workloads, and high injury risks. The purpose of this study was to gain an increased understanding of how systematic occupational safety and health management is performed and which factors that influence motivation for occupational safety and health improvements in the Swedish equine sector. An explanatory sequential mixed-methods study, based on quantitative data from questionnaires and qualitative data from semi-structured interviews, was conducted. Various statistical analyses were performed to obtain quantitative data and an abductive applied thematic analysis was applied for the qualitative data. The results indicate that both intrinsic motivators, i.e. attitudes, values, and influence, as well as contextual factors such as motivational management, occupational culture, and workplace resources, influence compliance in systematic occupational safety and health management and participation in occupational safety and health improvements, which in turn affect workplace outcomes regarding safety and health. The positive relationship found between an implemented and functioning systematic occupational safety and health management and employee motivation for occupational safety and health improvements indicate the importance of employee involvement and participation. Understanding the motivational factors for occupational safety and health improvements from an employee perspective is an important step to creating healthy and sustainable workplaces.
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| 3. |
- Catton, Erin A., et al.
(author)
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Human CEACAM1 is targeted by a Streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis
- 2023
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In: Nature Communications. - 2041-1723. ; 14
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Journal article (peer-reviewed)abstract
- Life-threatening bacterial infections in women after childbirth, known as puerperal sepsis, resulted in classical epidemics and remain a global health problem. While outbreaks of puerperal sepsis have been ascribed to Streptococcus pyogenes, little is known about disease mechanisms. Here, we show that the bacterial R28 protein, which is epidemiologically associated with outbreaks of puerperal sepsis, specifically targets the human receptor CEACAM1. This interaction triggers events that would favor the development of puerperal sepsis, including adhesion to cervical cells, suppression of epithelial wound repair and subversion of innate immune responses. High-resolution structural analysis showed that an R28 domain with IgI3-like fold binds to the N-terminal domain of CEACAM1. Together, these findings demonstrate that a single adhesin-receptor interaction can drive the pathogenesis of bacterial sepsis and provide molecular insights into the pathogenesis of one of the most important infectious diseases in medical history.
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| 4. |
- Lindahl, Gunnar
(author)
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Subdominance in Antibody Responses : Implications for Vaccine Development
- 2020
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In: Microbiology and Molecular Biology Reviews. - 1092-2172. ; 85:1
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Research review (peer-reviewed)abstract
- SUMMARYVaccines work primarily by eliciting antibodies, even when recovery from natural infection depends on cellular immunity. Large efforts have therefore been made to identify microbial antigens that elicit protective antibodies, but these endeavors have encountered major difficulties, as witnessed by the lack of vaccines against many pathogens. This review summarizes accumulating evidence that subdominant protein regions, i.e., surface-exposed regions that elicit relatively weak antibody responses, are of particular interest for vaccine development. This concept may seem counterintuitive, but subdominance may represent an immune evasion mechanism, implying that the corresponding region potentially is a key target for protective immunity. Following a presentation of the concepts of immunodominance and subdominance, the review will present work on subdominant regions in several major human pathogens: the protozoan Plasmodium falciparum, two species of pathogenic streptococci, and the dengue and influenza viruses. Later sections are devoted to the molecular basis of subdominance, its potential role in immune evasion, and general implications for vaccine development. Special emphasis will be placed on the fact that a whole surface-exposed protein domain can be subdominant, as demonstrated for all of the pathogens described here. Overall, the available data indicate that subdominant protein regions are of much interest for vaccine development, not least in bacterial and protozoal systems, for which antibody subdominance remains largely unexplored.
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| 5. |
- von Beek, Christopher, et al.
(author)
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A two-step activation mechanism enables mast cells to differentiate their response between extracellular and invasive enterobacterial infection
- 2024
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- Mast cells localize to mucosal tissues and contribute to innate immune defense against infection. How mast cells sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium (S.Tm) and other related enterobacteria, here we show that mast cells can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S.Tm and mast cells colocalize in the mouse gut during acute Salmonella infection. Toll-like Receptor 4 (TLR4) sensing of extracellular S.Tm, or pure lipopolysaccharide, causes a modest induction of cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S.Tm invasion of both mouse and human mast cells triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to drive the full-blown mast cell response. Supernatants from S.Tm-infected mast cells boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that mast cells can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.
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| 6. |
- von Beek, Christopher, et al.
(author)
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A two-step activation mechanism enables mast cells to differentiate their response between extracellular and invasive enterobacterial infection
- 2024
-
In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
-
Journal article (peer-reviewed)abstract
- Mast cells localize to mucosal tissues and contribute to innate immune defense against infection. How mast cells sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium (S.Tm) and other related enterobacteria, here we show that mast cells can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S.Tm and mast cells colocalize in the mouse gut during acute Salmonella infection. Toll-like Receptor 4 (TLR4) sensing of extracellular S.Tm, or pure lipopolysaccharide, causes a modest induction of cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S.Tm invasion of both mouse and human mast cells triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to drive the full-blown mast cell response. Supernatants from S.Tm-infected mast cells boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that mast cells can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.
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| 7. |
- Westin, Johan, 1965, et al.
(author)
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Management of hepatitis B virus infection, updated Swedish guidelines
- 2020
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In: Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 2374-4243. ; 52:1, s. 1-22
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Journal article (peer-reviewed)abstract
- Despite access to effective antiviral drugs and vaccines, hepatitis B virus (HBV) infection remains a major health issue worldwide. HBV is highly infectious and may cause chronic infection, progressive liver damage, hepatocellular cancer (HCC) and death. Early diagnosis, proper management and timing of treatment are crucial. The Swedish Reference group for Antiviral Treatment (RAV) here provides updated evidence-based guidelines for treatment and management of HBV infection which may be applicable also in other countries. Tenofovir alafenamide (TAF) has been introduced as a novel treatment option and new principles regarding indication and duration of treatment and characterization of hepatitis B have been gradually introduced which justifies an update of the previous guidelines from 2007. Updated guidelines on HCC surveillance in HBV-infected patients, treatment and prophylaxis for patients undergoing liver transplantation as well as management of pregnant women and children with HBV infection are also provided.
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