| 1. |
- Bernhard, Sara, et al.
(författare)
-
The outer membrane protein OlpA contributes to Moraxella catarrhalis serum resistance via interaction with factor H and the alternative pathway.
- 2014
-
Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 210:8, s. 1306-1310
-
Tidskriftsartikel (refereegranskat)abstract
- Factor H is an important complement regulator of the alternative pathway commonly recruited by pathogens for increased survival in the human host. The respiratory pathogen Moraxella catarrhalis that resides in the mucosa is highly serum resistant and causes otitis media in children and respiratory tract infections in individuals with underlying diseases. In this study, we show that M. catarrhalis binds factor H via the outer membrane protein OlpA. M. catarrhalis serum resistance was dramatically decreased in the absence of either OlpA or factor H, demonstrating that this inhibition of the alternative pathway significantly contributes to the virulence of M. catarrhalis.
|
|
| 2. |
|
|
| 3. |
- Bonagas, Nadilly, et al.
(författare)
-
Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
-
Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
-
Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
|
|
| 4. |
- Carlsson, Julia, et al.
(författare)
-
Att planera för hela skogslandskapet : utmaningar och möjligheter
- 2016
-
Rapport (populärvet., debatt m.m.)abstract
- Skogens många värden behöver samplaneras och sättas i sitt sammanhang utifrån ett landskapsperspektiv. Vi intervjuade skogsägare och skogliga intressenter om hur de ser på skogens värden, äganderätten och skogspolitiska förutsättningar, samt synen på att samarbeta och ta hänsyn till varandras intressen. Vi utgår från behov identifierade i planeringsprocesser som inkluderar många deltagare och intressen, när det gäller att förbättrakommunikation, information och mötesplatser. Vi ser tre möjliga verktyg för att skapa förutsättningar för ett landskapsperspektiv i planeringen av skogens värden: en landskapslots, en samverkansarena, samt utformningen och användandet av skogsbruksplanen.
|
|
| 5. |
- Carlsson, Julia, et al.
(författare)
-
Opportunites for Integrated Landscape Planning : the Broker, the Arena, the Tool
- 2017
-
Ingår i: Landscape Online. - 1865-1542. ; 55, s. 1-20
-
Tidskriftsartikel (refereegranskat)abstract
- As an integrated social and ecological system, the forest landscape includes multiple values. The need for a landscape approach in land use planning is being increasingly advocated in research, policy and practice. This paper explores how institutional conditions in the forest policy and management sector can be developed to meet demands for a multifunctional landscape perspective. Departing from obstacles recognised in collaborative planning literature, we build an analytical framework which is operationalised in a Swedish context at municipal level. Our case illustrating this is Vilhelmina Model Forest, where actual barriers and opportunities for a multiple-value landscape approach are identified through 32 semi-structured interviews displaying stakeholders’ views on forest values, ownership rights and willingness to consider multiple values, forest policy and management premises, and collaboration. As an opportunity to overcome the barriers, we suggest and discuss three key components by which an integrated landscape planning approach could be realized in forest management planning: the need for a landscape coordinator (broker), the need for a collaborative forum (arena), and the development of the existing forest management plan into an advanced multifunctional landscape plan (tool).
|
|
| 6. |
- Conti, David, V, et al.
(författare)
-
Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
-
Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
-
Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
|
|
| 7. |
- Deknuydt, Florence, et al.
(författare)
-
Diversion of the host humoral response: a novel virulence mechanism of Haemophilus influenzae mediated via outer membrane vesicles.
- 2014
-
Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 95:6, s. 983-991
-
Tidskriftsartikel (refereegranskat)abstract
- The respiratory tract pathogen Haemophilus influenzae frequently causes infections in humans. In parallel with all Gram-negative bacteria, H. influenzae has the capacity to release OMV. The production of these nanoparticles is an intriguing and partly unexplored phenomenon in pathogenesis. Here, we investigated how purified human peripheral blood B lymphocytes respond to OMV derived from unencapsulated, i.e., NTHi and the nonpathogenic Haemophilus parainfluenzae. We found that H. influenzae OMV directly interacted with the IgD BCR, as revealed by anti-IgD pAb and flow cytometry. Importantly, H. influenzae OMV-induced cellular activation via IgD BCR cross-linking and TLR9 resulted in a significant proliferative response. OMV isolated from the related species H. parainfluenzae did not, however, interact with B cells excluding that the effect by H. influenzae OMV was linked to common membrane components, such as the LOS. We also observed an up-regulation of the cell surface molecules CD69 and CD86, and an increased IgM and IgG secretion by B cells incubated with H. influenzae OMV. The Igs produced did not recognize H. influenzae, suggesting a polyclonal B cell activation. Interestingly, the density of the cell surface receptor TACI was increased in the presence of OMV that sensitized further the B cells to BAFF, resulting in an enhanced IgG class-switch. In conclusion, the ability of NTHi OMV to activate B cells in a T cell-independent manner may divert the adaptive humoral immune response that consequently promotes bacterial survival within the human host.
|
|
| 8. |
- Fagerqvist, Therese, et al.
(författare)
-
Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation
- 2013
-
Ingår i: Journal of Neurochemistry. - : Wiley-Blackwell. - 0022-3042 .- 1471-4159. ; 126:1, s. 131-144
-
Tidskriftsartikel (refereegranskat)abstract
- Inclusions of intraneuronal alpha-synuclein (-synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of -synuclein is a central feature of the disease pathogenesis. Among the different -synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large -synuclein oligomers were generated. These antibodies, which do not bind amyloid-beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in -synuclein transgenic mice than linear epitope antibodies. An oligomer-selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of -synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of -synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer-selective -synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.
|
|
| 9. |
- Hallström, Teresia, et al.
(författare)
-
Immune Evasion of Moraxella catarrhalis Involves Ubiquitous Surface Protein A-Dependent C3d Binding.
- 2011
-
Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 186, s. 3120-3129
-
Tidskriftsartikel (refereegranskat)abstract
- The complement system plays an important role in eliminating invading pathogens. Activation of complement results in C3b deposition (opsonization), phagocytosis, anaphylatoxin (C3a, C5a) release, and consequently cell lysis. Moraxella catarrhalis is a human respiratory pathogen commonly found in children with otitis media and in adults with chronic obstructive pulmonary disease. The species has evolved multiple complement evasion strategies, which among others involves the ubiquitous surface protein (Usp) family consisting of UspA1, A2, and A2 hybrid. In the present study, we found that the ability of M. catarrhalis to bind C3 correlated with UspA expression and that C3 binding contributed to serum resistance in a large number of clinical isolates. Recombinantly expressed UspA1 and A2 inhibit both the alternative and classical pathways, C3b deposition, and C3a generation when bound to the C3 molecule. We also revealed that the M. catarrhalis UspA-binding domain on C3b was located to C3d and that the major bacterial C3d-binding domains were within UspA1(299-452) and UspA2(165-318). The interaction with C3 was not species specific since UspA-expressing M. catarrhalis also bound mouse C3 that resulted in inhibition of the alternative pathway of mouse complement. Taken together, the binding of C3 to UspAs is an efficient strategy of Moraxella to block the activation of complement and to inhibit C3a-mediated inflammation.
|
|
| 10. |
- Lindström, Veronica, et al.
(författare)
-
Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] α-synuclein mice
- 2014
-
Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 69, s. 134-143
-
Tidskriftsartikel (refereegranskat)abstract
- Several lines of evidence suggest that accumulation of aggregated alpha-synuclein (α-synuclein) in the central nervous system (CNS) is an early pathogenic event and therefore a suitable therapeutic target in Parkinson’s disease and other Lewy body disorders. In recent years, animal studies have indicated immunotherapy with antibodies directed against α-synuclein as a promising novel treatment strategy. Since large α-synuclein oligomers, or protofibrils, have been demonstrated to possess pronounced cytotoxic properties, such species should be particularly attractive as therapeutic targets. An α-synuclein protofibril-selective monoclonal antibody, mAb47, was evaluated in the (Thy-1)-h[A30P] α-synuclein transgenic mouse model, featuring an age- and motor dysfunction-associated increase of α-synuclein protofibrils in the CNS. As measured by ELISA, mAb47-treated mice displayed significantly lower levels of both soluble and membrane-associated protofibrils in the spinal cord. In addition, a trend for increased survival as a result of reduced motor symptoms was observed with antibody treatment. Taken together, this study demonstrates reduced levels of pathogenic α-synuclein and indicates a reduction of motor dysfunction in transgenic mice upon peripheral administration of an α-synuclein protofibril-selective antibody. Thus, immunotherapy with antibodies targeting toxic α-synuclein species holds promise as a future disease-modifying treatment in Parkinson’s disease and related disorders.
|
|
| 11. |
- Löfroth, Therese, et al.
(författare)
-
Land-sparing benefits biodiversity while land-sharing benefits ecosystem services : Stakeholders’ perspectives on biodiversity conservation strategies in boreal forests
- 2024
-
Ingår i: Ambio. - : Springer Nature. - 0044-7447 .- 1654-7209. ; 53:1, s. 20-33
-
Tidskriftsartikel (refereegranskat)abstract
- Biodiversity conservation and economic profit from forests can be combined by various land-sparing and land-sharing approaches. Using a semi-structured survey, we evaluated support for scenarios representing contrasting conservation strategies in a managed boreal forest landscape. Land-sparing approaches were supported by the conservation organisation, regional administrations and the forest company, mainly motivated by the benefit for biodiversity based on ecological theory. Land-sharing approaches were supported by one recreational organisation, some municipalities and the forest owners’ association, mainly motivated by the delivery of ecosystem services. Stakeholder groups using certain ecosystem services had motivations that we related to an anthropocentric mindset, while others focused more on species conservation, which can be related both to an anthropocentric or an ecocentric mindsets. Forest conservation planning should consider stakeholders’ preferences to handle land-use conflicts. Since reaching consensus among multiple stakeholders seems unfeasible, a combination of land-sparing and land-sharing approaches is probably the best compromise.
|
|
| 12. |
- Movert, Elin, et al.
(författare)
-
Streptococcal M protein promotes IL-10 production by cGAS-independent activation of the STING signaling pathway
- 2018
-
Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7374 .- 1553-7366. ; 14:3
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 13. |
- Möllenkvist, Andrea, et al.
(författare)
-
The Moraxella catarrhalis immunoglobulin D-binding protein MID has conserved sequences and is regulated by a mechanism corresponding to phase variation
- 2003
-
Ingår i: Journal of Bacteriology. - : American Society for Microbiology. - 0021-9193 .- 1098-5530. ; 185:7, s. 2285-2295
-
Tidskriftsartikel (refereegranskat)abstract
- The prevalence of the Moraxella catarrhalis immunoglobulin D (IgD)-binding outer membrane protein MID and its gene was determined in 91 clinical isolates and in 7 culture collection strains. Eighty-four percent of the clinical Moraxella strains expressed MID-dependent IgD binding. The mid gene was detected in all strains as revealed by homology of the signal peptide sequence and a conserved area in the 3' end of the gene. When MID proteins from five different strains were compared, an identity of 65.3 to 85.0% and a similarity of 71.2 to 89.1% were detected. Gene analyses showed several amino acid repeat motifs in the open reading frames, and MID could be called a putative autotransport protein. Interestingly, homopolymeric [polyguanine [poly(G)]] tracts were detected at the 5' ends within the open reading frames. By flow cytometry, using human IgD and fluorescein isothiocyanate-conjugated anti-IgD polyclonal antibodies, most strains showed two peaks: one high- and one low-intensity peak. All isolates expressing high levels of MID had 1, 2, or 3 triplets of G's in their poly(G) tracts, while strains not expressing MID had 4, 7, 8, or 10 G's in their poly(G) tracts or point mutations causing a putative preterminated translation. Northern blot analysis revealed that the mid gene was regulated at the transcriptional level. Experiments with nonclumping variants of M. catarrhalis proved that bacteria lost their MID expression by removing a G in their poly(G) tracts. Moraxella strains isolated from the nasopharynx or from blood and sputum specimens expressed MID at approximately the same frequency. In addition, no variation was observed between strains of different geographical origins (Australia, Europe, Japan, or the United States). MID and the mid gene were found solely in M. catarrhalis, whereas related Neisseria and Moraxella species did not express MID. Taken together, MID appears to be a conserved protein that can be found in essentially all M. catarrhalis strains. Furthermore, MID is governed by poly(G) tracts when bacteria undergo phase variation.
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
- Nordström, Moa, 1982, et al.
(författare)
-
Pseudophakia and Lens Opacities in 70-Year-Olds in Gothenburg, Sweden; Gender Differences, Impact on Self-Reported Visual Function and Validation of Self-Reported Cataract and Pseudophakia
- 2022
-
Ingår i: Clinical Ophthalmology. - 1177-5483. ; 16, s. 3269-3281
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: The study aimed at determining the prevalence and sex differences in cataract, pseudophakia, lens opacities and self -reported cataract in 70-year-old people in Gothenburg, Sweden. The purpose was also to identify correlations between lens opacities, visual acuity and subjective visual function, and to validate self-reported cataract and cataract surgery.Patients and Methods: Population-based cross-sectional study where participants (n=1182) answered questions about self-reported diagnosis of cataract and cataract surgery. A total of 1139 subjects completed the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25), 560 subjects underwent ophthalmic examination including visual acuity and lens photography. t-test, Pearson chi-square and Mann-Whitney U-test were used for obtaining p-values. ANOVA (analysis of variances, Kruskal- Wallis, one-way) was used to compare VFQ-25 between 3 groups; no cataract, cataract and pseudophakia. To clarify the differences between specific pairs of groups post-hoc test (Bonferroni) was used after ANOVA.Results: Self-reported cataract was more common in women than in men (27.2% vs 19.1%, p=0.001, chi-square). Cataract surgery was reported by 16.3% of women and 12.6% of men (p=0.072). Upon eye examination, the prevalence of pseudophakia was 16.9% in women compared to 10.2% in men (p=0.020). The prevalence of cataract, including pseudophakia, was 31.9% in women versus 23.8% in men (p=0.033). Significant correlations (Spearman's rho) were found between lens opacities and visual acuity. Self-reported cataract surgery showed a very high specificity and high sensitivity. The composite score from NEI VFQ-25 was lower in people with pseudophakia than in people with/without cataract (p=0.012, Kruskal-Wallis).Conclusion: The prevalence of cataract including pseudophakia in 70-year-olds in Gothenburg is higher compared to previous studies in similar geographical areas. Also, it is more common in women than in men. The lack of significant sex differences in lens opacities may be due to cataract surgery at an earlier stage. Validation showed very good agreement between pseudophakia and self-reported cataract surgery.
|
|
| 17. |
- Nordström, Therése, et al.
(författare)
-
Human Siglec-5 Inhibitory Receptor and Immunoglobulin A (IgA) Have Separate Binding Sites in Streptococcal {beta} Protein.
- 2011
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 286:39, s. 33981-33991
-
Tidskriftsartikel (refereegranskat)abstract
- Sialic acid-binding immunoglobulin-like lectins (Siglecs) are receptors believed to be important for regulation of cellular activation and inflammation. Several pathogenic microbes bind specific Siglecs via sialic acid-containing structures at the microbial surface, interactions that may result in modulation of host responses. Recently, it was shown that the group B Streptococcus (GBS) binds to human Siglec-5 (hSiglec-5), an inhibitory receptor expressed on macrophages and neutrophils, via the IgA-binding surface β protein, providing the first example of a protein/protein interaction between a pathogenic microbe and a Siglec. Here we show that the hSiglec-5-binding part of β resides in the N-terminal half of the protein, which also harbors the previously determined IgA-binding region. We constructed bacterial mutants expressing variants of the β protein with non-overlapping deletions in the N-terminal half of the protein. Using these mutants and recombinant β fragments, we showed that the hSiglec-5-binding site is located in the most N-terminal part of β (B6N region; amino acids 1-152) and that the hSiglec-5- and IgA-binding domains in β are completely separate. We showed with BIAcore(TM) analysis that tandem variants of the hSiglec-5- and IgA-binding domains bind to their respective ligands with high affinity. Finally, we showed that the B6N region, but not the IgA-binding region of β, triggers recruitment of the tyrosine phosphatase SHP-2 to hSiglec-5 in U937 monocytes. Taken together, we have identified and isolated the first microbial non-sialic acid Siglec-binding region that can be used as a tool in studies of the β/hSiglec-5 interaction.
|
|
| 18. |
- Nordström, Therése, et al.
(författare)
-
Ionic binding of C3 to the human pathogen Moraxella catarrhalis is a unique mechanism for combating innate immunity
- 2005
-
Ingår i: Journal of Immunology. - 1550-6606. ; 175:6, s. 3628-3636
-
Tidskriftsartikel (refereegranskat)abstract
- Moraxella catarrhalis ubiquitous surface proteins A1 and A2 (UspA1/A2) interfere with the classical pathway of the complement system by binding C4b-binding protein. In this study we demonstrate that M. catarrhalis UspA1 and A2 noncovalently and in a dose-dependent manner bind both the third component of complement (C3) from EDTA-treated serum and methylamine-treated C3. In contrast, related Moraxella subspecies (n = 13) or other human pathogenic bacteria (n = 13) do not bind C3 or methylamine-treated C3. Experiments with recombinant proteins and M. catarrhalis mutants devoid of UspA1/A2 revealed that UspA1/A2 exert their actions by absorbing and neutralizing C3 from serum and restrain complement activation. UspA2 was responsible for most of the effect, and the Moraxella mutant lacking UspA2 was more sensitive to the lytic effect of human serum compared with the wild type. Interestingly, among the large number of bacteria analyzed, only M. catarrhalis has this unique ability to interfere with the innate immune system of complement by binding C3.
|
|
| 19. |
- Nordström, Therése
(författare)
-
MORAXELLA CATARRHALIS OUTER MEMBRANE PROTEINS AND INTERACTIONS WITH THE HUMAN IMMUNE SYSTEM
- 2005
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Moraxella catarrhalis is frequently colonizing the human respiratory tract, particularly in children. This gram-negative bacterium has during the last two decades been recognized as a pathogen causing otitis media in children and lower respiratory tract infections in adults with predisposing conditions such as chronic obstructive pulmonary disease (COPD). The virulence determinants of M. catarrhalis are believed to be the lipooligosaccharide and the outer membrane proteins. Three important outer membrane proteins are Moraxella IgD-binding protein (MID), the ubiquitous surface proteins (Usp) A1 and A2. MID is an adhesin and it binds to IgD in a non-immune manner. We show that the mid gene was highly conserved, and that the MID expression varied without relation to the anatomical site of isolation or geographical origin of the isolates. The expression was also shown to be controlled by a poly(G)tract downstream of the startcodon. The region of MID with essentially preserved IgD-binding was determined to be located between the amino acid residues 962-1200 and was designated MID962-1200. MID962-1200 was shown to be a tetramer in native conditions and interestingly, this tetrameric form bound IgD 23-fold more efficiently than the monomeric form. Moreover, MID962-1200 stimulated purified B cells to proliferate independently of T cells. However, addition of IL-4 or IL-2 was required for efficient proliferation. We have also shown that M. catarrhalis interferes with both the classical and the alternative pathway of the complement system. It bound to the fluid phase inhibitor C4b-binding protein (C4BP) and the binding was mediated through UspA1 and UspA2. Importantly, C4BP retained its activity when bound to the surface of M. catarrhalis and was thus able to inhibit the activation through the classical pathway. We also showed that M. catarrhalis have the capacity to absorb C3 from serum independently of complement activation and UspA2 was determined to be the major binder of C3. In summary, MID is widely distributed among different M. catarrhalis strains. The IgD-binding region of MID is located between the amino acid residues 962-1200 and stimulates B cells independently of T cells. Finally, the M. catarrhalis outer membrane proteins UspA1 and UspA2 interfere with the complement system by binding C4BP and C3.
|
|
| 20. |
- Nordström, Therése, et al.
(författare)
-
The emerging pathogen Moraxella catarrhalis interacts with complement inhibitor C4b binding protein through ubiquitous surface proteins A1 and A2
- 2004
-
Ingår i: Journal of Immunology. - 1550-6606. ; 173:7, s. 4598-4606
-
Tidskriftsartikel (refereegranskat)abstract
- Moraxella catarrhalis ubiquitous surface protein A2 (UspA2) mediates resistance to the bactericidal activity of normal human serum. In this study, an interaction between the complement fluid phase regulator of the classical pathway, C4b binding protein (C4BP), and M. catarrhalis mutants lacking UspA1 and/or UspA2 was analyzed by flow cytometry and a RIA. Two clinical isolates of M. catarrhalis expressed UspA2 at a higher density than UspA1. The UspA1 mutants showed a decreased C4BP binding (37.6% reduction), whereas the UspA2-deficient Moraxella mutants displayed a strongly reduced (94.6%) C4BP? binding compared with the wild type. In addition, experiments with recombinantly expressed UspA1(50-770) and UspA2(30-539) showed that C4BP (range, 1-1000 nM) bound to the two proteins in a dose-dependent manner. The equilibrium constants (K-D) for the USpA1(50-770) and USpA(30-539) interactions with a single subunit of C4BP were 13 muM and 1.1 muM, respectively. The main isoform of COP contains seven identical alpha-chains and one beta-chain linked together with disulfide bridges, and the a-chains contain eight complement control protein (CCP) modules. The UspA1 and A2 bound to the a-chain of C4BP, and experiments with C4BP lacking CCP2, CCP5, or CCP7 showed that these three CCPs were important for the Usp binding. Importantly, C4BP bound to the surface of M. catarrhalis retained its cofactor activity as determined by analysis of C4b degradation. Taken together, M. catarrhalis interferes with the classical complement activation pathway by binding C4BP to UspA1 and UspA2.
|
|
| 21. |
- Nordström, Therése, et al.
(författare)
-
The IgD-binding domain of the Moraxella IgD-binding protein MID (MID962-1200) activates human B cells in the presence of T cell cytokines.
- 2006
-
Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 79:2, s. 319-329
-
Tidskriftsartikel (refereegranskat)abstract
- Moraxella catarrhalis immunoglobulin D (IgD)-binding protein (MID) is an outer membrane protein with specific affinity for soluble and cell-bound human IgD. Here, we demonstrate that mutated M. catarrhalis strains devoid of MID show a 75% decreased activation of human B cells as compared with wild-type bacteria. In contrast to MID-expressing Moraxella, the MID-deficient Moraxella mutants did not bind to human CD19(+) IgD(+) B cells. The smallest MID fragment with preserved IgD-binding capacity comprises 238 amino acids (MID962-1200). To prove the specificity of MID962-1200 for IgD, a Chinese hamster ovary (CHO) cell line expressing membrane-anchored human IgD was manufactured. MID962-1200 bound strongly to the recombinant IgD on CHO cells. Moreover, MID962-1200 stimulated peripheral blood lymphocyte (PBL) proliferation 5- and 15-fold at 0.1 and 1.0 mu g/ml, respectively. This activation could be blocked completely by antibodies directed against the CD40 ligand (CD154). MID962-1200 also activated purified B cells in the presence of interleukin (IL)-2 or IL-4. An increased IL-6 production was seen after stimulation with MID962-1200, as revealed by a human cytokine protein array. MID962-1200 fused to green fluorescent protein (GFP) bound to human B cells and activated PBL to the same degree as MID962-1200 Taken together, MID is the only IgD-binding protein in Moraxella. Furthermore, the novel T cell-independent antigen MID962-1200 may, together with MID962-1200-GFP, be considered as promising reagents in the study of IgD-dependent B cell activation.
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
- Schaar, Viveka, et al.
(författare)
-
Group A streptococci are protected from amoxicillin-mediated killing by vesicles containing β-lactamase derived from Haemophilus influenzae.
- 2014
-
Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 1460-2091 .- 0305-7453. ; 69:1, s. 117-120
-
Tidskriftsartikel (refereegranskat)abstract
- Group A streptococci (GAS) cause, among other infections, pharyngotonsillitis in children. The species is frequently localized with the Gram-negative respiratory pathogens non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis, which both produce outer membrane vesicles (OMVs). The aim of this study was to investigate whether OMVs isolated from NTHi contain functional β-lactamase and whether the OMVs hydrolyse amoxicillin and thus protect GAS from killing by the antibiotic.
|
|
| 25. |
- Schaar, Viveka, et al.
(författare)
-
Moraxella catarrhalis outer membrane vesicles carry beta-lactamase and promote survival of Streptococcus pneumoniae and Haemophilus influenzae by inactivating amoxicillin.
- 2011
-
Ingår i: Antimicrobial Agents and Chemotherapy. - 1098-6596. ; 55, s. 3845-3853
-
Tidskriftsartikel (refereegranskat)abstract
- Moraxella catarrhalis is a common pathogen found in children with upper respiratory tract infections, and in patients with chronic obstructive pulmonary disease during exacerbations. The bacterial species is often isolated together with Streptococcus pneumoniae and Haemophilus influenzae. Outer membrane vesicles (OMV) are released by M. catarrhalis and contain phospholipids, adhesins, and immunomodulatory compounds such as lipooligosaccharide. We have recently shown that M. catarrhalis OMV exist in patients upon nasopharyngeal colonization. As virtually all M. catarrhalis are β-lactamase positive, the goal of this study was to investigate whether M. catarrhalis OMV carry β-lactamase, and to analyze if OMV consequently can prevent amoxicillin-induced killing. Recombinant RH4 β-lactamase was produced and antibodies were raised in rabbits. Transmission electron microscopy, flow cytometry and Western blots verified that OMV carried β-lactamase. Moreover, enzyme assays revealed that M. catarrhalis OMV contained active β-lactamase. OMV (25 μg/ml) incubated with amoxicillin for 1 hr completely hydrolyzed amoxicillin at concentrations up to 2.5 μg/ml. In functional experiments, pre-incubation of amoxicillin (10xMIC) with M. catarrhalis OMV fully rescued amoxicillin-susceptible M. catarrhalis, S. pneumoniae and type b or non-typeable H. influenzae from β-lactam-induced killing. Our results suggest that the presence of amoxicillin-resistant M. catarrhalis originating from β-lactamase-containing OMV may pave the way for respiratory pathogens that by definition are susceptible to β-lactam antibiotics.
|
|
| 26. |
- Singh, Kalpana, et al.
(författare)
-
Haemophilus influenzae reside in tonsills and use IgD binding as an evasion strategy.
- 2014
-
Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 209:9, s. 1418-1428
-
Tidskriftsartikel (refereegranskat)abstract
- Haemophilus influenzae (Hi) causes respiratory tract infections and is also considered as a commensal, particularly in pre-school children. Tonsils from patients (n=617) undergoing tonsillectomy due to chronical infection or hypertrophy were examined. We found that 51 % of tonsils were positive for Hi, and in 95 % of cases analysed in detail (n=39) Hi resided intracellularly in the core tonsillar tissue. Patients harboured several intracellular unique strains and the majority were non-typeable Hi (NTHi). Interestingly, the isolated NTHi bound soluble immunoglobulin (Ig) D at the constant heavy chain domain 1 as revealed by recombinant IgD/IgG chimeras. NTHi also interacted with B lymphocytes via the IgD B cell receptor resulting in internalization of bacteria, T-cell independent activation via Toll like receptor 9, and differentiation into non-NTHi specific IgM producing cells. Taken together, IgD-binding NTHi leads to an unspecific immune response and may support the bacteria to circumvent the host defense.
|
|
| 27. |
- Sténs, Anna, 1976-, et al.
(författare)
-
In the eye of the stakeholder : the challenges of governing social forest values
- 2016
-
Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 45:2, s. 87-99
-
Tidskriftsartikel (refereegranskat)abstract
- This study examines which kinds of social benefits derived from forests are emphasised by Swedish stakeholders and what governance modes and management tools they accept. Our study shows that there exists a great variety among stakeholders’ perceptions of forests’ social values, where tourism and recreation is the most common reference. There are also differences in preferred governance modes and management where biomass and bioenergy sectors advocate business as usual (i.e. framework regulations and voluntarism) and other stakeholders demand rigid tools (i.e. coercion and targeting) and improved landscape planning. This divide will have implications for future policy orientations and require deliberative policy processes and improved dialogue among stakeholders and authorities. We suggest that there is a potential for these improvements, since actors from almost all stakeholder groups support local influence on governance and management, acknowledged and maintained either by the authorities, i.e. targeting, or by the stakeholders themselves, i.e. voluntarism.
|
|
| 28. |
|
|
| 29. |
|
|
