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Antibodies damage the resilience of fimbriae, causing them to be stiff and tangled
Umeå University, Faculty of Science and Technology, Department of Physics. (The Biophysics and Biophotonics group)
Umeå University, Faculty of Science and Technology, Department of Physics. (The Biophysics and Biophotonics group)
Enteric Diseases Department, Naval Medical Research Center, Silver Spring, MD, 20910, USA.
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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2017 (English)In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 199, no 1, e00665-16Article in journal (Refereed) Published
Abstract [en]

As adhesion fimbriae are a major virulence factor for many pathogenic Gram-negative bacteria, they are also potential targets for antibodies. Fimbriae are commonly required for initiating the colonization that leads to disease, and their success as adhesion organelles lies in their ability to both initiate and sustain bacte- rial attachment to epithelial cells. The ability of fimbriae to unwind and rewind their helical filaments presumably reduces their detachment from tissue surfaces with the shear forces that accompany significant fluid flow. Therefore, the disruption of func- tional fimbriae by inhibiting this resilience should have high potential for use as a vaccine to prevent disease. In this study, we show that two characteristic biome- chanical features of fimbrial resilience, namely, the extension force and the exten- sion length, are significantly altered by the binding of antibodies to fimbriae. The fimbriae that were studied are normally expressed on enterotoxigenic Escherichia coli, which are a major cause of diarrheal disease. This alteration in biomechanical properties was observed with bivalent polyclonal antifimbrial antibodies that recog- nize major pilin subunits but not with the Fab fragments of these antibodies. Thus, we propose that the mechanism by which bound antibodies disrupt the uncoiling of natural fimbria under force is by clamping together layers of the helical filament, thereby increasing their stiffness and reducing their resilience during fluid flow. In addition, we propose that antibodies tangle fimbriae via bivalent binding, i.e., by binding to two individual fimbriae and linking them together. Use of antibodies to disrupt physical properties of fimbriae may be generally applicable to the large number of Gram-negative bacteria that rely on these surface-adhesion molecules as an essential virulence factor.

I M P O R T A N C E Our study shows that the resiliency of colonization factor antigen I (CFA/I) and coli surface antigen 2 (CS2) fimbriae, which are current targets for vac- cine development, can be compromised significantly in the presence of antifimbrial antibodies. It is unclear how the humoral immune system specifically interrupts in- fection after the attachment of enterotoxigenic Escherichia coli (ETEC) to the epithe- lial surface. Our study indicates that immunoglobulins, in addition to their well- documented role in adaptive immunity, can mechanically damage the resilience of fimbriae of surface-attached ETEC, thereby revealing a new mode of action. Our data suggest a mechanism whereby antibodies coat adherent and free-floating bacteria to impede fimbrial resilience. Further elucidation of this possible mechanism is likely to inform the development and refinement of preventive vaccines against ETEC diar- rhea. 

Place, publisher, year, edition, pages
2017. Vol. 199, no 1, e00665-16
Keyword [en]
pili, IgG, vaccine, CFA/I, CS2, optical tweezers
National Category
Biophysics Immunology Other Physics Topics
Identifiers
URN: urn:nbn:se:umu:diva-119692DOI: 10.1128/JB.00665-16ISI: 000391288200018OAI: oai:DiVA.org:umu-119692DiVA: diva2:922835
Funder
Swedish Research Council, 621- 2013-5379Swedish Research Council, 2012-4638NIH (National Institute of Health), RR025434
Note

Originally published in manuscript form with title "Antibodies damage fimbrial resilience, making them stiff and tangled"

Available from: 2016-04-25 Created: 2016-04-25 Last updated: 2017-02-15Bibliographically 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
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)
Opponent
Supervisors
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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