title: Antibodies Damage the Resilience of Fimbriae, Causing Them To Be Stiff and Tangled.
abstract: 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 bacterial 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 functional 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 biomechanical features of fimbrial resilience, namely, the extension force and the extension 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 recognize 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.
  
  
  
  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 vaccine development, can be compromised significantly in the presence of antifimbrial antibodies. It is unclear how the humoral immune system specifically interrupts infection after the attachment of enterotoxigenic Escherichia coli (ETEC) to the epithelial 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 diarrhea.
authors: Department of Physics, Umeå University, Umeå, Sweden.
authors: Bhupender
authors: B
authors: Singh
authors: Department of Physics, Umeå University, Umeå, Sweden.
authors: Narges
authors: N
authors: Mortezaei
authors: Enteric Diseases Department, Naval Medical Research Center, Silver Spring, Maryland, USA.
authors: Stephen J
authors: SJ
authors: Savarino
authors: Laboratory for Molecular Infection Medicine Sweden (MIMS), Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors: Bernt Eric
authors: BE
authors: Uhlin
authors: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: Esther
authors: E
authors: Bullitt
authors: Department of Physics, Umeå University, Umeå, Sweden magnus.andersson@umu.se.
authors: Magnus
authors: M
authors: Andersson
mesh_terms: D018830:Adhesins, Escherichia coli / Q000235:genetics / Q000378:metabolism; D000907:Antibodies, Bacterial / Q000502:physiology*; D001422:Bacterial Adhesion / Q000502:physiology; D001696:Biomechanical Phenomena; D004926:Escherichia coli / Q000166:cytology / Q000378:metabolism*; D036781:Fimbriae Proteins / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D018625:Microscopy, Atomic Force
chemical_list: D018830:Adhesins, Escherichia coli; D000907:Antibodies, Bacterial; C022924:colonization factor antigens; D036781:Fimbriae Proteins
keywords: CFA/I; CS2; IgG; optical tweezers; pili; vaccine