Julie Bouckaert

Bacterial Adhesion

Keywords
cell adhesion - bacterial infection - protein structure and function - protein-carbohydrate interactions - fimbriae and pili

Science Pathogenic bacteria assemble virulence factors on their surfaces to adhere to host epithelia. Such organelles on the bacterial cell envelope are pili or fimbriae, constructed as linear or helical polymers of proteins (pilins) with an immunoglubulin-fold. The assembly of most fimbriae occurs on the outer cell membrane of the bacteria via the chaperone/usher pathway. Many pili present a sticky protein at the tip, by a two-domain adhesin (TDA) made of a pilin and a receptor-binding domain. Others present an invasin (eg. Dr fimbriae from uropathogenic Escherichia coli) and still others contain the adhesive capacity in every pilin (SDA or single domain adhesin). The major pilin and adhesin FaeG is a first example of an SDA for which a crystal structure has been determined. FaeG production was targeted to plant chloroplasts rendering high yields of potential edible vaccine. FaeG forms F4 fimbriae that are the major colonization factors associated with porcine neonatal and postweaning diarrhoea caused by enterotoxigenic E. coli. It turns out that the lack of fimbrial chaperone in the chloroplasts results into very stable strand-swapped dimers of FaeG. The 1.9 Å crystal structure revealed how FaeG combines the structural requirements of a major fimbrial subunit with its adhesive role by grafting an additional domain on its Ig-like core.

A few hundreds of pili with a TDA are typically utilized by the bacterium to reach its glycosylated receptors, either glycoproteins or glycolipids on the epithelium of mammalian host cells. Each type of pilus is characterized by a particular carbohydrate specificity. Variants of a given pilus can express adhesins with the same monosaccharide specificity but with different fine specificities. These variants steer pathogenicity depending on the presence of suitable receptors. The attachment through the fimbrial adhesin assists the bacteria in colonizing the target tissue of the host and to resist cleansing mechanisms that are presented by the host. The first step in urinary tract infections caused by uropathogenic E. coli (85 % of the infections) is the mannose-specific attachment of the type-1 fimbrial adhesin FimH to the integral membrane glycoprotein uroplakin Ia. We identified inhibitors with an 100-fold higher affinity than mannose that block the adhesion of the bacteria in vitro as well as in vivo. Our findings spark new ideas for the development and rational design of anti-adhesive drugs to prevent anticipated and recurrent UTIs.