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Antibodies damage fimbrial resilience, making them stiff and tangled
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).
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Since adhesion fimbriae are a major virulence factor for many pathogenic Gram-negative bacteria, theyare potential targets for antibodies. Fimbriae are commonly required to initiate colonization leading todisease, and their success as adhesion organelles lies in their ability to both initiate and sustain bacterialattachment to epithelial cells. The ability of fimbriae to unwind and rewind their helical filament ispresumably reducing their detachment from tissue surfaces by shear forces during significant fluid flow.Disruption of functional fimbriae by inhibiting this resilience therefore should have great therapeuticpotential. In this study, we show that two characteristic biomechanical features of fimbrial resilience, theextension force and the extension length, are significantly altered by antibody-binding to fimbriaenormally expressed on enterotoxigenic Escherichia coli that are a major cause of diarrheal disease. Thiseffect was observed with bivalently binding polyclonal anti-fimbrial antibodies but not with Fab fragmentsrecognizing major pilin subunits. Thus, we propose that the mechanism by which bound antibodies disruptnatural fimbria uncoiling under force is by clamping together layers of the helical filament, therebyincreasing their stiffness and reducing their resilience during fluid flow. In addition, we propose thatantibodies tangle fimbriae via bivalent binding, by binding to two individual fimbriae and linking themtogether. Use of antibodies to disrupt physical properties of fimbriae may be generally applicable to thelarge number of Gram-negative bacteria that rely on these surface-adhesion molecules as an essentialvirulence factor.

Keyword [en]
pili, IgG, vaccine, CFA/I, CS2, optical tweezers
National Category
Biophysics
Identifiers
URN: urn:nbn:se:umu:diva-119692OAI: oai:DiVA.org:umu-119692DiVA: diva2:922835
Available from: 2016-04-25 Created: 2016-04-25 Last updated: 2016-04-29
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
Biophysics
Identifiers
urn:nbn:se:umu:diva-119694 (URN)978-91-7601-464-6 (ISBN)
Public defence
2016-05-20, Naturvetarhuset N420, Umeå, 13:00 (English)
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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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Department of PhysicsMolecular Infection Medicine Sweden (MIMS)
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