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Antibody-mediated disruption of the mechanics of CS20 fimbriae of enterotoxigenic Escherichia coli
Umeå University, Faculty of Science and Technology, Department of Physics.
Umeå University, Faculty of Science and Technology, Department of Physics.
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, 13678Article in journal (Refereed) Published
Abstract [en]

Preventive vaccines against enterotoxigenic Escherichia coli (ETEC) are being developed, many of which target common fimbrial colonization factors as the major constituent, based on empirical evidence that these function as protective antigens. Particularly, passive oral administration of ETEC anti-fimbrial antibodies prevent ETEC diarrhea. Little is, however, known regarding the specific mechanisms by which intestinal antibodies against ETEC fimbriae function to prevent disease. Using coli surface antigen 20 (CS20) fimbriae as a model ETEC colonization factor, we show using force spectroscopy that anti-fimbrial antibodies diminish fimbrial elasticity by inhibiting their natural capacity to unwind and rewind. In the presence of anti-CS20 antibodies the force required to unwind a single fimbria was increased several-fold and the extension length was shortened several-fold. Similar measurements in the presence of anti-CS20 Fab fragments did not show any effect, indicating that bivalent antibody binding is required to reduce fimbrial elasticity. Based on these findings, we propose a model for an in-vivo mechanism whereby antibody-mediated disruption of the biomechanical properties of CS20 fimbriae impedes sustained adhesion of ETEC to the intestinal mucosal surface. Further elucidation of the role played by intestinal antibodies in mechanical disruption of fimbrial function may provide insights relevant to ETEC vaccine development.

Place, publisher, year, edition, pages
2015. Vol. 5, 13678
National Category
Biophysics Immunology Other Physics Topics Nano Technology
URN: urn:nbn:se:umu:diva-108176DOI: 10.1038/srep13678ISI: 000361806400001OAI: diva2:851301
Swedish Research Council
Available from: 2015-09-04 Created: 2015-09-04 Last updated: 2016-04-29Bibliographically approved
In thesis
1. Exploring the impact of antibodies on the mechanics of bacterial fimbriae
Open this publication in new window or tab >>Exploring the impact of antibodies on the mechanics of bacterial fimbriae
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The discovery of antibiotics in 1928 seemed like a win in the battle against infectious diseases. But, the ability of bacterial pathogens to adapt to these life-saving medicines was underestimated. The bacterial evolution, indeed, led to the emergence of antibiotic resistance as soon as the clinical consumption of antibiotics started. Today, certain bacteria including some strains of the gram-negative Escherichia coli are resistant to all major antibiotics. To overcome this problem, identifying new therapeutic targets in bacteria is essential, which necessitates scrutinizing the bacterial infection mechanism. An initial step in the bacterial infection mechanism is identification of and adherence to host tissue. Thus, blocking bacterial adhesion is considered as a potential target in the battle against infectious diseases. Gram-negative bacteria generally establish their adhesion by variety of proteinaceous structures known as fimbriae. The strains of Escherichia coli associated with gastrointestinal and urinary tract infections, for instance, colonize their host via a variety of adhesion fimbriae. These adhesion organelles are comprised of subunits assembled into a helix-like structure with remarkable biomechanical properties. For example, fimbriae can be significantly extended under force and are therefore very flexible. Fimbrial flexibility is considered to be beneficial for attachment and adhesion of bacteria in fluidic regions.

The aims of this thesis are: to provide insight into the structural and biomechanical differences of fimbriae expressed by enterotoxigenic and uropathogenic Escherichia coli, and to investigate how fimbrial mechanics are affected in the presence of anti-fimbrial antibodies. To achieve these aims we put together data acquired using different technical approaches. We used force measuring optical tweezers to characterize the force-extension responses of fimbriae in the absence and presence of antibodies. High-resolution imaging was employed to explore the structural features of fimbriae as well as monitoring the antibody-fimbriae interactions. Our results demonstrate that each type of fimbria explored shows unique force spectroscopy responses. For example, the fimbriae expressed by uropathogenic Escherichia coli require a higher unwinding force in comparison to enterotoxigenic Escherichia coli fimbriae. These observations suggest that bacteria adapt to the environment wherein they establish colonization by expressing fimbriae with different biophysical features. Such evolutionary adaptation can thereby help in the bacterial adhesion process. Furthermore, we found that antibodies significantly alter the biophysical features of fimbriae, implying that antibodies significantly interfere with the mechanics of fimbriae. We suggest further elucidation of how antibodies disrupt fimbrial mechanics, providing insights for the development of antibody-based therapeutics.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2016. 70 p.
National Category
urn:nbn:se:umu:diva-119694 (URN)978-91-7601-464-6 (ISBN)
Public defence
2016-05-20, Naturvetarhuset N420, Umeå, 13:00 (English)
Available from: 2016-04-29 Created: 2016-04-25 Last updated: 2016-04-29Bibliographically approved

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Singh, BhupenderMortezaei, NargesUhlin, Bernt EricAndersson, Magnus
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