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Arnqvist, Anna
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Publications (10 of 35) Show all publications
Lekmeechai, S., Su, Y.-C., Brant, M., Alvarado-Kristensson, M., Vallström, A., Obi, I., . . . Riesbeck, K. (2018). Helicobacter pylori Outer Membrane Vesicles Protect the Pathogen From Reactive Oxygen Species of the Respiratory Burst. Frontiers in Microbiology, 9, Article ID 1837.
Open this publication in new window or tab >>Helicobacter pylori Outer Membrane Vesicles Protect the Pathogen From Reactive Oxygen Species of the Respiratory Burst
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2018 (English)In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 9, article id 1837Article in journal (Refereed) Published
Abstract [en]

Outer membrane vesicles (OMVs) play an important role in the persistence of Helicobacter pylori infection. Helicobacter OMVs carry a plethora of virulence factors, including catalase (KatA), an antioxidant enzyme that counteracts the host respiratory burst. We found KatA to be enriched and surface-associated in OMVs compared to bacterial cells. This conferred OMV-dependent KatA activity resulting in neutralization of H2O2 and NaClO, and rescue of surrounding bacteria from oxidative damage. The antioxidant activity of OMVs was abolished by deletion of KatA. In conclusion, enrichment of antioxidative KatA in OMVs is highly important for efficient immune evasion.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
H. pylori, KatA, outer membrane vesicles, oxidative burst, reactive oxygen species
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-152205 (URN)10.3389/fmicb.2018.01837 (DOI)000443976200001 ()30245670 (PubMedID)
Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-10-25Bibliographically approved
Skoog, E. C., Padra, M., Åberg, A., Gideonsson, P., Obi, I., Quintana-Hayashi, M. P., . . . Linden, S. K. (2017). BabA dependent binding of Helicobacter pylori to human gastric mucins cause aggregation that inhibits proliferation and is regulated via ArsS. Scientific Reports, 7, Article ID 40656.
Open this publication in new window or tab >>BabA dependent binding of Helicobacter pylori to human gastric mucins cause aggregation that inhibits proliferation and is regulated via ArsS
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 40656Article in journal (Refereed) Published
Abstract [en]

Mucins in the gastric mucus layer carry a range of glycan structures, which vary between individuals, can have antimicrobial effect or act as ligands for Helicobacter pylori. Mucins from various individuals and disease states modulate H. pylori proliferation and adhesin gene expression differently. Here we investigate the relationship between adhesin mediated binding, aggregation, proliferation and adhesin gene expression using human gastric mucins and synthetic adhesin ligand conjugates. By combining measurements of optical density, bacterial metabolic activity and live/dead stains, we could distinguish bacterial aggregation from viability changes, enabling elucidation of mechanisms behind the anti-prolific effects that mucins can have. Binding of H. pylori to Leb-glycoconjugates inhibited the proliferation of the bacteria in a BabA dependent manner, similarly to the effect of mucins carrying Leb. Furthermore, deletion of arsS lead to a decrease in binding to Leb-glycoconjugates and Leb-decorated mucins, accompanied by decreased aggregation and absence of anti-prolific effect of mucins and Leb-glycoconjugates. Inhibition of proliferation caused by adhesin dependent binding to mucins, and the subsequent aggregation suggests a new role of mucins in the host defense against H. pylori. This aggregating trait of mucins may be useful to incorporate into the design of adhesin inhibitors and other disease intervention molecules.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-132309 (URN)10.1038/srep40656 (DOI)000392344400001 ()28106125 (PubMedID)
Available from: 2017-04-07 Created: 2017-04-07 Last updated: 2018-06-09Bibliographically approved
Bugaytsova, J. A., Björnham, O., Chernov, Y. A., Gideonsson, P., Henriksson, S., Mendez, M., . . . Boren, T. (2017). Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence. Cell Host and Microbe, 21(3), 376-389
Open this publication in new window or tab >>Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence
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2017 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, no 3, p. 376-389Article in journal (Refereed) Published
Abstract [en]

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-132788 (URN)10.1016/j.chom.2017.02.013 (DOI)000396375600023 ()28279347 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2019-05-24Bibliographically approved
Moonens, K., Gideonsson, P., Subedi, S., Bugaytsova, J., Romao, E., Mendez, M., . . . Remaut, H. (2016). Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori. Cell Host and Microbe, 19(1), 55-66
Open this publication in new window or tab >>Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori
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2016 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 19, no 1, p. 55-66Article in journal (Refereed) Published
Abstract [en]

The Helicobacter pylori adhesin BabA binds mucosal ABO/Le b blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown. We generated X-ray structures of representative BabA isoforms that reveal a polymorphic, three-pronged Le(b) binding site. Two diversity loops, DL1 and DL2, provide adaptive control to binding affinity, notably ABO versus O bg preference. H. pylori strains can switch bg preference with single DL1 amino acid substitutions, and can coexpress functionally divergent BabA isoforms. The anchor point for receptor binding is the embrace of an ABO fucose residue by a disulfide-clasped loop, which is inactivated by reduction. Treatment with the redox-active pharmaceutic N-acetylcysteine lowers gastric mucosal neutrophil infiltration in H. pylori-infected Le(b)-expressing mice, providing perspectives on possible H. pylori eradication therapies.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-117839 (URN)10.1016/j.chom.2015.12.004 (DOI)000369839900010 ()26764597 (PubMedID)
Available from: 2016-04-04 Created: 2016-03-04 Last updated: 2018-06-07Bibliographically approved
Turkina, M. V., Olofsson, A., Magnusson, K.-E., Arnqvist, A. & Vikstrom, E. (2015). Helicobacter pylori vesicles carrying CagA localize in the vicinity of cell-cell contacts and induce histone H1 binding to ATP in epithelial cells. FEMS Microbiology Letters, 362(11), Article ID fnv076.
Open this publication in new window or tab >>Helicobacter pylori vesicles carrying CagA localize in the vicinity of cell-cell contacts and induce histone H1 binding to ATP in epithelial cells
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2015 (English)In: FEMS Microbiology Letters, ISSN 0378-1097, E-ISSN 1574-6968, Vol. 362, no 11, article id fnv076Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori produces outer membrane vesicles (OMV), delivering bacterial substances including the oncogenic cytotoxin-associated CagA protein to their surroundings. We investigated the effects of H. pylori OMV carrying CagA (OMV-CagA) on cell junctions and ATP-binding proteome of epithelial monolayers, using proteomics, mass spectrometry and imaging. OMV-CagA localized in close vicinity of ZO-1 tight junction protein and induced histone H1 binding to ATP. We suggest the expression of novel events in the interactions between H. pylori OMV and epithelia, which may have an influence on host gene transcription and lead to different outcomes of an infection and development of cancer.

Keywords
Helicobacter pylori, outer membrane vesicles, CagA, ATP-proteome, histone H1, epithelial cell-cell junctions
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-106572 (URN)10.1093/femsle/fnv076 (DOI)000356890900007 ()
Available from: 2015-07-20 Created: 2015-07-20 Last updated: 2018-06-07Bibliographically approved
Åberg, A., Gideonsson, P., Vallström, A., Olofsson, A., Öhman, C., Rakhimova, L., . . . Arnqvist, A. (2014). A Repetitive DNA Element Regulates Expression of the Helicobacter pylori Sialic Acid Binding Adhesin by a Rheostat-like Mechanism. PLoS Pathogens, 10(7), Article ID e1004234.
Open this publication in new window or tab >>A Repetitive DNA Element Regulates Expression of the Helicobacter pylori Sialic Acid Binding Adhesin by a Rheostat-like Mechanism
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2014 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 10, no 7, article id e1004234Article in journal (Refereed) Published
Abstract [en]

During persistent infection, optimal expression of bacterial factors is required to match the ever-changing host environment. The gastric pathogen Helicobacter pylori has a large set of simple sequence repeats (SSR), which constitute contingency loci. Through a slipped strand mispairing mechanism, the SSRs generate heterogeneous populations that facilitate adaptation. Here, we present a model that explains, in molecular terms, how an intergenically located T-tract, via slipped strand mispairing, operates with a rheostat-like function, to fine-tune activity of the promoter that drives expression of the sialic acid binding adhesin, SabA. Using T-tract variants, in an isogenic strain background, we show that the length of the T-tract generates multiphasic output from the sabA promoter. Consequently, this alters the H. pylori binding to sialyl-Lewis x receptors on gastric mucosa. Fragment length analysis of post-infection isolated clones shows that the T-tract length is a highly variable feature in H. pylori. This mirrors the host-pathogen interplay, where the bacterium generates a set of clones from which the best-fit phenotypes are selected in the host. In silico and functional in vitro analyzes revealed that the length of the T-tract affects the local DNA structure and thereby binding of the RNA polymerase, through shifting of the axial alignment between the core promoter and UP-like elements. We identified additional genes in H. pylori, with T- or A-tracts positioned similar to that of sabA, and show that variations in the tract length likewise acted as rheostats to modulate cognate promoter output. Thus, we propose that this generally applicable mechanism, mediated by promoter-proximal SSRs, provides an alternative mechanism for transcriptional regulation in bacteria, such as H. pylori, which possesses a limited repertoire of classical trans-acting regulatory factors.

National Category
Physiology Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-91641 (URN)10.1371/journal.ppat.1004234 (DOI)000340551000026 ()24991812 (PubMedID)
Available from: 2014-08-13 Created: 2014-08-13 Last updated: 2018-06-07Bibliographically approved
Olofsson, A., Nygård Skalman, L., Obi, I., Lundmark, R. & Arnqvist, A. (2014). Uptake of Helicobacter pylori vesicles is facilitated by clathrin-dependent and clathrin-independent endocytic pathways. mBio, 5(3), e00979-14
Open this publication in new window or tab >>Uptake of Helicobacter pylori vesicles is facilitated by clathrin-dependent and clathrin-independent endocytic pathways
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2014 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 5, no 3, p. e00979-14-Article in journal (Refereed) Published
Abstract [en]

UNLABELLED: Bacteria shed a diverse set of outer membrane vesicles that function as transport vehicles to deliver effector molecules and virulence factors to host cells. Helicobacter pylori is a gastric pathogen that infects half of the world's population, and in some individuals the infection progresses into peptic ulcer disease or gastric cancer. Here we report that intact vesicles from H. pylori are internalized by clathrin-dependent endocytosis and further dynamin-dependent processes, as well as in a cholesterol-sensitive manner. We analyzed the uptake of H. pylori vesicles by gastric epithelial cells using a method that we refer to as quantification of internalized substances (qIS). The qIS assay is based on a near-infrared dye with a cleavable linker that enables the specific quantification of internalized substances after exposure to reducing conditions. Both chemical inhibition and RNA interference in combination with the qIS assay showed that H. pylori vesicles enter gastric epithelial cells via both clathrin-mediated endocytosis and additional endocytic processes that are dependent on dynamin. Confocal microscopy revealed that H. pylori vesicles colocalized with clathrin and dynamin II and with markers of subsequent endosomal and lysosomal trafficking. Interestingly, however, knockdown of components required for caveolae had no significant effect on internalization and knockdown of components required for clathrin-independent carrier (CLIC) endocytosis increased internalization of H. pylori vesicles. Furthermore, uptake of vesicles by both clathrin-dependent and -independent pathways was sensitive to depletion, but not sequestering, of cholesterol in the host cell membrane suggesting that membrane fluidity influences the efficiency of H. pylori vesicle uptake.

IMPORTANCE: Bacterial vesicles act as long-distance tools to deliver toxins and effector molecules to host cells. Vesicles can cause a variety of host cell responses via cell surface-induced cell signaling or internalization. Vesicles of diverse bacterial species enter host cells via different endocytic pathways or via membrane fusion. With the combination of a fluorescence-based quantification assay that quantifies internalized vesicles in a large number of cells and either chemical inhibition or RNA interference, we show that clathrin-mediated endocytosis is the major pathway for uptake of Helicobacter pylori vesicles and that lipid microdomains of the host cell membrane affect uptake of vesicles via clathrin-independent pathways. Our results provide important insights about membrane fluidity and its important role in the complex process that directs the H. pylori vesicle to a specific endocytic pathway. Understanding the mechanisms that operate in vesicle-host interactions is important to fully recognize the impact of vesicles in pathogenesis.

National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-90953 (URN)10.1128/mBio.00979-14 (DOI)000338875900050 ()24846379 (PubMedID)
Available from: 2014-07-04 Created: 2014-07-04 Last updated: 2018-06-07Bibliographically approved
Ohno, T., Vallström, A., Rugge, M., Ota, H., Graham, D. Y., Arnqvist, A. & Yamaoka, Y. (2011). Effects of blood group antigen-binding adhesin expression during Helicobacter pylori infection of Mongolian gerbils. Journal of Infectious Diseases, 203(5), 726-735
Open this publication in new window or tab >>Effects of blood group antigen-binding adhesin expression during Helicobacter pylori infection of Mongolian gerbils
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2011 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 203, no 5, p. 726-735Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori outer membrane proteins, such as the blood group antigen-binding adhesin (BabA), are associated with severe pathological outcomes. However, the in vivo role of BabA during long-term infection is not clear. In this study, Mongolian gerbils were infected with H. pylori and necropsied continuously during 18 months. Bacterial clones were recovered and analyzed for BabA expression, Leb-binding activity, and adhesion to gastric mucosa. BabA expression was completely absent by 6 months post-infection. Loss of BabA expression was attributable to nucleotide changes within the babA gene that resulted in a truncated BabA. In response to the infection, changes in the epithelial glycosylation pattern were observed that were similar to responses observed in humans and monkeys. Furthermore, infections with BabA-expressing and BabA-nonexpressing H. pylori showed no differences in colonization, but infection with the BabA-expressing strain exhibited histological changes and increased inflammatory cell infiltration. This suggests that BabA expression contributes to severe mucosal injury.

Keywords
outer-membrane proteins; baba; inflammation; activation; attachment; gastritis; gene; oipa
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-41100 (URN)10.1093/infdis/jiq090 (DOI)21227917 (PubMedID)
Available from: 2011-03-17 Created: 2011-03-17 Last updated: 2018-06-08Bibliographically approved
Basmarke-Wehelie, R., Sjolinder, H., Jurkowski, W., Elofsson, A., Arnqvist, A., Engstrand, L., . . . Jonsson, A.-B. (2011). The Complement Regulator CD46 Is Bactericidal to Helicobacter pylori and Blocks Urease Activity. Gastroenterology, 141(3), 918-928
Open this publication in new window or tab >>The Complement Regulator CD46 Is Bactericidal to Helicobacter pylori and Blocks Urease Activity
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2011 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 141, no 3, p. 918-928Article in journal (Refereed) Published
Abstract [en]

Background & Aims: CD46 is a C3b/C4b binding complement regulator and a receptor  for several human pathogens. We examined the interaction between CD46 and Helicobacter pylori (a bacterium that colonizes the human gastric mucosa and causes gastritis), peptic ulcers, and cancer.

Methods: Using gastric epithelial cells, we analyzed a set of H pylori strains and mutants for their ability to interact with CD46 and/or influence CD46 expression. Bacterial interaction with full-length CD46 and small CD46 peptides was evaluated by flow cytometry, fluorescence microscopy, enzyme-linked immunosorbent assay, and bacterial survival analyses.

Results: H pylori infection caused shedding of CD46 into the extracellular environment. A soluble form of CD46 bound to H pylori and inhibited growth, in a dose- and time-dependent manner, by interacting with urease and alkyl hydroperoxide reductase, which are essential bacterial pathogenicity-associated factors. Binding of CD46 or CD46-derived synthetic peptides blocked theurease activity and ability of bacteria to survive in acidic environments. Oral administration of one CD46 peptide eradicated H pylori from infected mice.

Conclusions: CD46 is an antimicrobial agent that can eradicate H pylori. CD46 peptides might be developed to treat H pylori infection.

Place, publisher, year, edition, pages
Baltimore: Williams & Wilkins Co, 2011
Keywords
AhpC, Stomach Cancer, Bacterial Infection, Antibiotic
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-47390 (URN)10.1053/j.gastro.2011.05.009 (DOI)
Available from: 2011-09-26 Created: 2011-09-20 Last updated: 2018-06-08Bibliographically approved
Olofsson, A., Vallström, A., Petzold, K., Tegtmeyer, N., Schleucher, J., Carlsson, S., . . . Arnqvist, A. (2010). Biochemical and functional characterization of Helicobacter pylori vesicles. Molecular Microbiology, 77(6), 1539-1555
Open this publication in new window or tab >>Biochemical and functional characterization of Helicobacter pylori vesicles
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2010 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 77, no 6, p. 1539-1555Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori can cause peptic ulcer disease and/or gastric cancer. Adhesion of bacteria to the stomach mucosa is an important contributor to the vigor of infection and resulting virulence. H. pylori adheres primarily via binding of BabA adhesins to ABO/Lewis b (Leb) blood group antigens and the binding of SabA adhesins to sialyl-Lewis x/a (sLex/a) antigens. Similar to most Gram-negative bacteria, H. pylori continuously buds off vesicles and vesicles derived from pathogenic bacteria often include virulence-associated factors. Here we biochemically characterized highly purified H. pylori vesicles. Major protein and phospholipid components associated with the vesicles were identified with mass spectroscopy and NMR. A subset of virulence factors present was confirmed by immunoblots. Additional functional and biochemical analysis focused on the vesicle BabA and SabA adhesins and their respective interactions to human gastric epithelium. Vesicles exhibit heterogeneity in their protein composition, which were specifically studied in respect to the BabA adhesin. We also demonstrate that the oncoprotein, CagA, is associated with the surface of H. pylori vesicles. Thus, we have explored mechanisms for intimate H. pylori vesicle-host interactions and found that the vesicles carry effector-promoting properties that are important to disease development.

Place, publisher, year, edition, pages
Wiley, 2010
Identifiers
urn:nbn:se:umu:diva-35586 (URN)10.1111/j.1365-2958.2010.07307.x (DOI)000281831400018 ()20659286 (PubMedID)
Available from: 2010-08-24 Created: 2010-08-24 Last updated: 2018-06-08Bibliographically approved
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