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Sharafutdinov, I., Tegtmeyer, N., Rohde, M., Olofsson, A., Ur Rehman, Z., Arnqvist, A. & Backert, S. (2024). Campylobacter jejuni surface-bound protease HtrA, but not the secreted protease nor protease in shed membrane vesicles, disrupts epithelial cell-to-cell junctions. Cells, 13(3), Article ID 224.
Öppna denna publikation i ny flik eller fönster >>Campylobacter jejuni surface-bound protease HtrA, but not the secreted protease nor protease in shed membrane vesicles, disrupts epithelial cell-to-cell junctions
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2024 (Engelska)Ingår i: Cells, E-ISSN 2073-4409, Vol. 13, nr 3, artikel-id 224Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Fundamental functions of the intestinal epithelium include the digestion of food, absorption of nutrients, and its ability to act as the first barrier against intruding microbes. Campylobacter jejuni is a major zoonotic pathogen accounting for a substantial portion of bacterial foodborne illnesses. The germ colonizes the intestines of birds and is mainly transmitted to humans through the consumption of contaminated poultry meat. In the human gastrointestinal tract, the bacterium triggers campylobacteriosis that can progress to serious secondary disorders, including reactive arthritis, inflammatory bowel disease and Guillain–Barré syndrome. We recently discovered that C. jejuni serine protease HtrA disrupts intestinal epithelial barrier functions via cleavage of the tight and adherens junction components occludin, claudin-8 and E-cadherin. However, it is unknown whether epithelial damage is mediated by the secreted soluble enzyme, by HtrA contained in shed outer-membrane vesicles (OMVs) or by another mechanism that has yet to be identified. In the present study, we investigated whether soluble recombinant HtrA and/or purified OMVs induce junctional damage to polarized intestinal epithelial cells compared to live C. jejuni bacteria. By using electron and confocal immunofluorescence microscopy, we show that HtrA-expressing C. jejuni bacteria trigger efficient junctional cell damage, but not soluble purified HtrA or HtrA-containing OMVs, not even at high concentrations far exceeding physiological levels. Instead, we found that only bacteria with active protein biosynthesis effectively cleave junctional proteins, which is followed by paracellular transmigration of C. jejuni through the epithelial cell layer. These findings shed new light on the pathogenic activities of HtrA and virulence strategies of C. jejuni.

Ort, förlag, år, upplaga, sidor
MDPI, 2024
Nyckelord
Campylobacter, E-cadherin, occludin, serine protease HtrA, tight junctions
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-222651 (URN)10.3390/cells13030224 (DOI)001161305800001 ()38334616 (PubMedID)2-s2.0-85184714047 (Scopus ID)
Forskningsfinansiär
Cancerfonden, 2018/474
Tillgänglig från: 2024-04-19 Skapad: 2024-04-19 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
Åberg, A., Gideonsson, P., Bhat, A., Ghosh, P. & Arnqvist, A. (2024). Molecular insights into the fine-tuning of pH-dependent ArsR-mediated regulation of the SabA adhesin in Helicobacter pylori. Nucleic Acids Research, 52(10), 5572-5595
Öppna denna publikation i ny flik eller fönster >>Molecular insights into the fine-tuning of pH-dependent ArsR-mediated regulation of the SabA adhesin in Helicobacter pylori
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2024 (Engelska)Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 52, nr 10, s. 5572-5595Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Adaptation to variations in pH is crucial for the ability of Helicobacter pylori to persist in the human stomach. The acid responsive two-component system ArsRS, constitutes the global regulon that responds to acidic conditions, but molecular details of how transcription is affected by the ArsR response regulator remains poorly understood. Using a combination of DNA-binding studies, in vitro transcription assays, and H. pylori mutants, we demonstrate that phosphorylated ArsR (ArsR-P) forms an active protein complex that binds DNA with high specificity in order to affect transcription. Our data showed that DNA topology is key for DNA binding. We found that AT-rich DNA sequences direct ArsR-P to specific sites and that DNA-bending proteins are important for the effect of ArsR-P on transcription regulation. The repression of sabA transcription is mediated by ArsR-P with the support of Hup and is affected by simple sequence repeats located upstream of the sabA promoter. Here stochastic events clearly contribute to the fine-tuning of pH-dependent gene regulation. Our results reveal important molecular aspects for how ArsR-P acts to repress transcription in response to acidic conditions. Such transcriptional control likely mediates shifts in bacterial positioning in the gastric mucus layer.

Ort, förlag, år, upplaga, sidor
Oxford University Press, 2024
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-226962 (URN)10.1093/nar/gkae188 (DOI)001186590200001 ()38499492 (PubMedID)2-s2.0-85195625493 (Scopus ID)
Forskningsfinansiär
Cancerfonden, 2018/474Vetenskapsrådet, 2014-4361
Tillgänglig från: 2024-06-24 Skapad: 2024-06-24 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
Nadeem, A., Alam, A., Toh, E., Myint, S. L., Ur Rehman, Z., Liu, T., . . . Wai, S. N. (2021). Phosphatidic acid-mediated binding and mammalian cell internalization of the Vibrio cholerae cytotoxin MakA. PLoS Pathogens, 17(3), Article ID 1009414.
Öppna denna publikation i ny flik eller fönster >>Phosphatidic acid-mediated binding and mammalian cell internalization of the Vibrio cholerae cytotoxin MakA
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2021 (Engelska)Ingår i: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 17, nr 3, artikel-id 1009414Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Vibrio cholerae is a noninvasive intestinal pathogen extensively studied as the causative agent of the human disease cholera. Our recent work identified MakA as a potent virulence factor of V. cholerae in both Caenorhabditis elegans and zebrafish, prompting us to investigate the potential contribution of MakA to pathogenesis also in mammalian hosts. In this study, we demonstrate that the MakA protein could induce autophagy and cytotoxicity of target cells. In addition, we observed that phosphatidic acid (PA)-mediated MakA-binding to the host cell plasma membranes promoted macropinocytosis resulting in the formation of an endomembrane-rich aggregate and vacuolation in intoxicated cells that lead to induction of autophagy and dysfunction of intracellular organelles. Moreover, we functionally characterized the molecular basis of the MakA interaction with PA and identified that the N-terminal domain of MakA is required for its binding to PA and thereby for cell toxicity. Furthermore, we observed that the ΔmakA mutant outcompeted the wild-type V. cholerae strain A1552 in the adult mouse infection model. Based on the findings revealing mechanistic insights into the dynamic process of MakA-induced autophagy and cytotoxicity we discuss the potential role played by the MakA protein during late stages of cholera infection as an anti-colonization factor.

Ort, förlag, år, upplaga, sidor
Public Library of Science, 2021
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-181991 (URN)10.1371/journal.ppat.1009414 (DOI)000631027700007 ()33735319 (PubMedID)2-s2.0-85103129339 (Scopus ID)
Tillgänglig från: 2021-04-12 Skapad: 2021-04-12 Senast uppdaterad: 2023-05-11Bibliografiskt granskad
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.
Öppna denna publikation i ny flik eller fönster >>Helicobacter pylori Outer Membrane Vesicles Protect the Pathogen From Reactive Oxygen Species of the Respiratory Burst
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2018 (Engelska)Ingår i: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 9, artikel-id 1837Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Frontiers Media S.A., 2018
Nyckelord
H. pylori, KatA, outer membrane vesicles, oxidative burst, reactive oxygen species
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-152205 (URN)10.3389/fmicb.2018.01837 (DOI)000443976200001 ()30245670 (PubMedID)2-s2.0-85053053080 (Scopus ID)
Tillgänglig från: 2018-10-25 Skapad: 2018-10-25 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
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.
Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 7, artikel-id 40656Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-132309 (URN)10.1038/srep40656 (DOI)000392344400001 ()28106125 (PubMedID)2-s2.0-85010288062 (Scopus ID)
Tillgänglig från: 2017-04-07 Skapad: 2017-04-07 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
Fjellström, M., Larsson, M., Edlund, A.-C., Kjellsson Lind, A., Ågren, P.-O., Eriksson, N., . . . Arvidsson, E. (2017). Fakultetsaudit: Intern bedömning av kvalitetsarbete för utbildning på grund- och avancerad nivå vid Teknisk-naturvetenskaplig fakultet hösten 2016. Umeå: Umeå universitet
Öppna denna publikation i ny flik eller fönster >>Fakultetsaudit: Intern bedömning av kvalitetsarbete för utbildning på grund- och avancerad nivå vid Teknisk-naturvetenskaplig fakultet hösten 2016
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2017 (Svenska)Rapport (Övrig (populärvetenskap, debatt, mm))
Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2017. s. 13
Nationell ämneskategori
Pedagogik
Identifikatorer
urn:nbn:se:umu:diva-169939 (URN)
Tillgänglig från: 2020-04-22 Skapad: 2020-04-22 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence
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2017 (Engelska)Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, nr 3, s. 376-389Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
CELL PRESS, 2017
Nationell ämneskategori
Mikrobiologi inom det medicinska området Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
urn:nbn:se:umu:diva-132788 (URN)10.1016/j.chom.2017.02.013 (DOI)000396375600023 ()28279347 (PubMedID)2-s2.0-85014795847 (Scopus ID)
Tillgänglig från: 2017-05-11 Skapad: 2017-05-11 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
Arnqvist, A. (2016). Roles of the BabA and the SabA adhesins in gastroduodenal diseases. In: Steffen Backert; Yoshio Yamaoka (Ed.), Helicobacter pylori research: from bench to bedside (pp. 143-164). Tokyo: Springer
Öppna denna publikation i ny flik eller fönster >>Roles of the BabA and the SabA adhesins in gastroduodenal diseases
2016 (Engelska)Ingår i: Helicobacter pylori research: from bench to bedside / [ed] Steffen Backert; Yoshio Yamaoka, Tokyo: Springer, 2016, s. 143-164Kapitel i bok, del av antologi (Refereegranskat)
Abstract [en]

Adhesion is an important prerequisite for colonization and it is the initial step in infections with pathogenic bacteria. Adherence to host epithelial surfaces is the result of bacterial surface proteins, called adhesins, and their specific interaction with cognate protein- or glycoconjugate receptors on the host cells. Often, the bacteria have a set of complementary adhesins that are specific for different host receptors. Alternative mechanism has been suggested to mediate H. pylori adhesion, and this chapter will focus on the two well-characterized adhesins BabA and SabA. In the healthy gastric mucosa, the Lewis b antigen (Leb) is present in the gastric epithelial lining of blood group O (H-antigen), B, and A individuals. H. pylori binding to ABO/Leb is mediated by the blood group antigen-binding BabA adhesin. As the inflammation develops, Leb is downregulated and the levels of sialylated antigens increase. Sialyl-Lewis x/a antigens (sLex/a) are specifically recognized by the H. pylori sialic acid-binding adhesin SabA. Even though bacterial adherence per se cannot cause disease, adherence is considered as a crucial step in pathogenesis since it is needed for bacterial delivery of effector molecules into the host cell. The presence of receptors and host-immune responses are two factors that differently affect adhesion. To achieve long-term colonization, H. pylori must regulate the expression of a cognate adhesin to fit the available receptors. Adhesion to the gastric epithelial cells promotes gain of nutrients, but too tight adhesion may be intimidating because of the risk of clearance by the bacteria for life-threatening immune responses. Thus, expression levels of the adhesins must be fine-tuned in accord to host receptor expression levels. This chapter will also discuss H. pylori adhesion in relation to severe gastric diseases.

Ort, förlag, år, upplaga, sidor
Tokyo: Springer, 2016
Nyckelord
ABO blood group antigen/Lewis b antigen (ABO/Leb), Adhesion, Blood group antigen-binding adhesin BabA, Helicobacter pylori, Homologous recombination, Sialic acid binding adhesin SabA, Sialyl-Lewis x antigen (sLex), Slipped-strand mispairing
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
urn:nbn:se:umu:diva-208542 (URN)10.1007/978-4-431-55936-8_6 (DOI)2-s2.0-84988556648 (Scopus ID)9784431559368 (ISBN)9784431559344 (ISBN)
Tillgänglig från: 2023-05-26 Skapad: 2023-05-26 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori
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2016 (Engelska)Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 19, nr 1, s. 55-66Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-117839 (URN)10.1016/j.chom.2015.12.004 (DOI)000369839900010 ()26764597 (PubMedID)2-s2.0-84959550066 (Scopus ID)
Tillgänglig från: 2016-04-04 Skapad: 2016-03-04 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
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.
Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: FEMS Microbiology Letters, ISSN 0378-1097, E-ISSN 1574-6968, Vol. 362, nr 11, artikel-id fnv076Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
Helicobacter pylori, outer membrane vesicles, CagA, ATP-proteome, histone H1, epithelial cell-cell junctions
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-106572 (URN)10.1093/femsle/fnv076 (DOI)000356890900007 ()2-s2.0-84948994436 (Scopus ID)
Tillgänglig från: 2015-07-20 Skapad: 2015-07-20 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
Projekt
Helicobacter pylori: Molekylära mekanismer som reglerar dynamiskt uttryck av vidhäftningsegenskaper [2008-03000_VR]; Umeå universitetStokastiska och styrda regulatoriska transkriptionsmekanismer hos Helicobacter pylori [2014-04361_VR]; Umeå universitet
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-5699-613X

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