Thomas Boren - Professor

Helicobacter pylori, Adhesion and Patho-Adaptation

Helicobacter pylori infection causes chronic active gastritis and peptic ulcer disease. In the western world, 10% of people (22.000.000 individuals) develop peptic ulcers. Furthermore, H. pylori infection is tightly correlated with development of gastric cancer with >500.000 mortalities/Y and, H. pylori has been defined a carcinogen by the WHO. The project studies protein-carbohydrate interactions that mediate adherence of H. pylori to stomach tissue. We focus on the Blood Group Antigen Binding Adhesin, BabA, which is the key player attachment protein that targets H. pylori binding to the stomach lining. Bacterial adherence is mediated by high-affinity (strong) binding to carbohydrates such as ABO antigens (displayed by the common ABO-blood group system). Our recent results demonstrate adaptation of H. pylori to changes in mucosal glycosylation patterns and, in addition, adaptation to ABO phenotypes in local population;

Our current projects and interests:

  • Structural identification of the detailed carbohydrate binding domains of the H. pylori BabA adhesin (crystals and NMR).
  • BabA will be analyzed for adaptation to host ABO phenotypes. Clones that have developed novel and adapted binding properties during infection of gastric mucosa will be identified by in vivo and in vitro selection.
  • H. pylori adhesin proteins will be developed into vaccine candidates. The animal model used is the transgenic "Lewis b mouse". Results can then be experimentally verified in human volunteers.

Group:

Jeanna Bugaytsova
Olena Rakhimova
Anna Shevtsova

Publications

Borén T., Falk P., Roth K.A., Larson G., and Normark S. (1993) Attachment of Helicobacter pylori to Human Gastric Epithelium Mediated by Blood Group Antigens. Science, 262, 1892-1895.

Ilver D., Arnqvist A., Ögren J., Frick I.-M., Kersulyte D., Incecik E. T., Berg D. E., Covacci A., Engstrand L., Borén T. (1998) Helicobacter pylori Adhesin Binding Fucosylated Histo-Blood Group Antigens Revealed by Retagging. Science, 279, 373-377.

Gerhard M, Lehn N, Neumayer N, Borén T, Rad R, Schepp W, Miehlke S, Classen M, Prinz C. (1999) Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc Natl Acad Sci U S A. 96(22):12778-83. 

Mahdavi J., Sondén B., Hurtig M., Olfat FO., Forsberg L., Roche N., Ångstrom J,. Larsson T., Teneberg S., Karlsson KA., Altraja S., Wadström T., Kersulyte D., Berg DE., Dubois A., Petersson C., Magnusson KE., Norberg T., Lindh F., Lundskog BB., Arnqvist A., Hammarström L., Borén T. (2002) Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science, 297, 573-578

Casswall T.H., Nilsson H.O., Björck L., Sjöstedt S., Xu L., Nord C.K., Borén T., Wadström T., Hammarström L. (2002) Bovine anti-Helicobacter pylori antibodies for oral immunotherapy. Scand J Gastroenterol. 37(12):1380-5. 

Aspholm-Hurtig M., Dailide G., Lahmann M., Kalia A., Ilver D., Roche N., Vikström S., Sjöström R., Lindén S., Bäckström A., Lundberg C., Arnqvist A., Mahdavi J., Nilsson U.J., Velapatino B., Gilman R.H., Gerhard M., Alarcon T., Lopez-Brea M., Nakazawa T., Fox J.G., Correa P., Dominguez-Bello M.G., Perez-Perez G.I., Blaser M.J., Normark S., Carlstedt I., Oscarson S., Teneberg S., Berg D.E., Borén T. (2004) Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin. Science, 305, 519-22

Aspholm M., Olfat FO., Nordén J., Sondén B., Lundberg C., Sjöström R., Altraja S., Odenbreit S., Haas R, Wadström T., Engstrand L., Semino-Mora C., Liu H., Dubois A., Teneberg S., Arnqvist A., Borén T. (2006) SabA is the H. pylori hemagglutinin and is polymorphic in binding to sialylated glycans. PLoS Pathog., 10:e110.

Aspholm M., Kalia A., Ruhl S., Schedin S., Arnqvist A., Lindén S., Sjöström R., Gerhard M., Semino-Mora C., Dubois A., Unemo M., Danielsson D., Teneberg S., Lee W.K., Berg D.E., Borén T. (2006) "Helicobacter pylori adhesion to carbohydrates" for Chapter 51, in the issue "Functional Glycobiology", edited by Minoru Fukuda. Methods in Enzymology, 417, 293-339.

Pant N., Hultberg ., Zhao Y., Svensson L., Pan-Hammarstrom Q., Johansen K., Pouwels P.H., Ruggeri F.M., Hermans P., Frenken L., Boren T., Marcotte H., Hammarstrom L. (2006) Lactobacilli expressing variable domain of llama heavy-chain antibody fragments (lactobodies) confer protection against rotavirus-induced diarrhea. J Infect Dis. 194(11):1580-8.

Dubois, A., Borén, T. (2007) Helicobacter pylori is invasive and it may be a facultative intracellular organism. Cell Microbiol., 5, 1108-16.

Lindén, S., Mahdavi, J., Semino-Mora, C., Carlstedt, I., Borén, T., Dubois, A. (2008) Role of ABO secretor status in mucosal innate immunity and H. pylori infection. PLoS Pathog. 1:e2.

Azevedo M, Eriksson S, Mendes N, Serpa J, Figueiredo C, Resende LP, Ruvoën-Clouet N, Haas R, Borén T, Le Pendu J, David L. (2008) Infection by Helicobacter pylori expressing the BabA adhesin is influenced by the secretor phenotype. J Pathol. 2008, 215(3):308-16.

Björnham O, Bugaytsova J, Borén T, Schedin S. (2009) Dynamic force spectroscopy of the Helicobacter pylori BabA-Lewis b binding. Biophys Chem. 143 (1-2), 102-5.

Ishijima N., Suzuki M., Ashida H., Ichikawa Y., Kanegae Y., Saito I., Borén T., Haas R., Sasakawa C., Mimuro H. (2011)
BabA-mediated Adherence Is a Potentiator of the Helicobacter pylori Type IV Secretion System Activity. J Biol Chem. 286, 25256-64.

Fei YY., Schmidt A., Bylund G., Johansson DX., Henriksson S., Lebrilla C., Solnick JV., Borén T.*, Zhu XD.* (2011) Use of Real-Time, Label-Free Analysis in Revealing Low-Affinity Binding to Blood Group 
Antigens by Helicobacter pylori. Anal Chem. 83, 6336-6341.                              

Mahdavi J., Royer PJ., Sjolinder HS., Azimi S., Self T., Stoof J., Wheldon LM., Brännström K., Wilson R., Moreton J., Moir JW., Sihlbom C., Borén T., Johnsson AB., Soultanas P., Ala’Aldeen DA. (2013) Pro-inflammatory cytokines can act as intracellular modulators of commensal bacterial virulence.  Open Biol. 3, 10,130048.

Messing J., Thöle C., Nieheus M., Shevtsova A., Glocker E., Borén T., Hensel A. (2014) Antiadhesive properties of Abelmoshus esculentus (Okra) immature fruit extract against Helicobacter pylori adhesion. PLoS One. 9, 1, e84836.

Åberg A, Gideonsson P, Vallström A, Olofsson A, Öhman C, Rakhimova L, Borén T, Engstrand L, Brännström K, Arnqvist A. (2014) A repetitive DNA element regulates expression of the Helicobacter pylori sialic acid binding adhesin by a rheostat-like mechanism. PLoS Pathog. 10(7).

Parreira P, Shi Q, Magalhaes A, Reis CA, Bugaytsova J, Borén T, Leckband D, Martins MC. (2014) Atomic force microscopy measurements reveal multiple bonds between Helicobacter pylori blood group antigen binding adhesin and Lewis b ligand. J R Soc Interface. 11, 101, 20141040.

Liu H., Fero J.B., Mendez M., Carpenter B.M., Servetas S.L., Rahman A., Goldman M.D., Boren T, Salama N.R., Merrell D.S., Dubois A. (2015) Analysis of a single Helicobacter pylori strain over a 10-year period in a primate model. Int J Med Microbiol. 305(3):392-403. 

Magalhães A., Rossez Y., Robbe-Masselot C., Maes E., Gomes J., Shevtsova A., Bugaytsova J., Borén T., Reis CA. (2016) Muc5ac gastric mucin glycosylation is shaped by FUT2 activity and functionally impacts Helicobacter pylori binding. Scientific Reports. 2016 6:25575. 

Saberi S., Schmidt A., Eybpoosh S., Esmaili M., Talebkhan Y., Mohajerani N., Oghalaie A., Eshagh Hosseini M., Mohagheghi M.A., Bugaytova J., Borén T*, Mohammadi M*. (2016) Helicobacter pylori Strains from Duodenal Ulcer Patients Exhibit Mixed babA/B Genotypes with Low Levels of BabA Adhesin and Lewis b Binding. Dig Dis Sci. 2016, 61(10):2868-77.

Moonens K., Gideonsson P., Subedi S., Bugaytsova J., Romaõ E., Mendez M., Nordén J., Fallah M., Rakhimova L., Shevtsova A., Lahmann M., Castaldo G., Brännström K., Coppens F., Lo AW., Ny T., Solnick J.V., Vandenbussche G., Oscarson S., Hammarström L., Arnqvist A., Berg D.E., Muyldermans S., Borén T*, Remaut H* (corresponding Authors*) (2016) Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori. Cell Host & Microbe. 2016, 19(1):55-66. 

Bugaytsova J.A., Björnham O., Chernov Y.A., Gideonsson P., Henriksson S., Mendez M., Sjöström R., Mahdavi J., Shevtsova A., Ilver D., Moonens K., Quintana-Hayashi M.P., Moskalenko R., Aisenbrey C., Bylund G., Schmidt A., Åberg A., Brännström K., Königer V., Vikström S, Rakhimova L, Hofer A, Ögren J, Liu H, Goldman MD, Whitmire JM, Ådén J., Younson J., Kelly C.G., Gilman R.H., Chowdhury A., Mukhopadhyay A.K., Nair G.B., Papadakos K.S., Martinez-Gonzalez B., Sgouras D.N., Engstrand L., Unemo M., Danielsson D., Suerbaum S., Oscarson S., Morozova-Roche L.A., Olofsson A., Gröbner G., Holgersson J., Esberg A., Strömberg N., Landström M, Eldridge A.M., Chromy B.A., Hansen L.M., Solnick J.V., Lindén SK., Haas R., Dubois A., Merrell DS., Schedin S., Remaut H., Arnqvist A., Berg DE., Borén T*. (2017) Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence. Cell Host & Microbe. 21(3):376-389. 

Kable ME., Hansen LM., Styer CM., Deck SL., Rakhimova O., Shevtsova A., Eaton KA., Martin ME., Gideonsson P., Borén T., Solnick JV. (2017) Host Determinants of Expression of the Helicobacter pylori BabA Adhesin. Scientific Reports. 2017, 7:46499. 

Hansen LM., Gideonsson P., Canfield DR., Boren T., and Solnick J. (2017) Dynamic Expression of the BabA Adhesin and its BabB Paralog During Helicobacter pylori Infection in Rhesus Macaques". Infect Immun. 2017, 85 (6). pii: e00094-17

Esberg A, Sheng N, Mårell L, Claesson R, Persson K, Borén T, Strömberg N. (2017) Streptococcus Mutans Adhesin Biotypes that Match and Predict Individual Caries Development. EBioMedicine. 2017, 205-215. doi: 10.1016/j.ebiom.2017.09.027.


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Umeå University
Medical Biochemistry and Biophysics
SE-901 87 Umeå, SWEDEN 

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