Abstract
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.
Highlights
Over the past decade, efforts have expanded to develop an effective vaccine against Enterotoxigenic Escherichia coli (ETEC) diarrhea to stem its resultant morbidity and mortality in young children and morbidity in travelers[11,12,13]
CS20 fimbriae are representative of an increasingly recognized class of fimbrial colonization factors expressed by ETEC
In this study we investigated at a single fimbria level if antibodies primarily directed against the fimbrial shaft can change the bio-mechanical properties of CS20
Summary
Efforts have expanded to develop an effective vaccine against ETEC diarrhea to stem its resultant morbidity and mortality in young children and morbidity in travelers[11,12,13]. The exact mechanisms by which antibodies prevent ETEC diarrhea have not been explicitly defined, though inhibition of epithelial attachment, bacterial aggregation, entrapment in mucus and enhanced bacterial clearance are rational possibilities[18] In recent work, another mechanism has been proposed by which antibodies might impair bacterial infection on mucosal surfaces. Results from in-vitro experiments show that shaft-specific antibodies can inhibit the unwinding and rewinding of P-fimbriae, a well-established virulence factor of uropathogenic E. coli (UPEC)[19]. This is the only instance reported to date in which antibodies cause biomechanical disruption of fimbrial elasticity, and it is unclear whether other classes of fimbriae would be affected. Since it has been proposed that fimbrial unwinding and rewinding may play an important role modulating bacterial adhesion[18,24], our findings have implications for the development and refinement of ETEC vaccines
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