Pseudomonas aeruginosa pili bind to asialoGM1 which is increased on the surface of cystic fibrosis epithelial cells.

Abstract

The basis for the unique association of Pseudomonas aeruginosa and the cystic fibrosis (CF) lung has remained obscure despite major advances in the understanding of the molecular genetic cause of this disease. There is evidence to suggest that abnormalities in CF transmembrane conductance regulator function result in alterations in the glycosylation of epithelial components. The number ofasialoGMl residues, as representative of a class of glycolipids which contain a GalNAcB14Gal sequence for P. aeruginosa attachment, was quantified by flow cytometric studies of respiratory epithelial cells in primary culture from both CF patients and normal subjects. Superficial asialoGMl was detected on 12% of the CF cells as compared with 2.9% of the cells from normal control subjects (P = 0.03, x' = 4.73), and more asialoGMl residues were exposed on CF cells after modification by P. aeruginosa exoproducts. AsialoGMl, but not the sialylated glycolipid GM1, was demonstrated to be a receptor for I2I-labeled P. aeruginosa pilin, a major adhesin for this organism, and exogenous asialoGMl was found to competitively inhibit P. aeruginosa adherence to epithelial cells, thus, confirming the biological role of the asialoGMl receptor. Quantitative and qualitative differences in the sialylation of superficial glycolipids in CF epithelial cells may directly contribute to the colonization of the CF lung by P. aeruginosa. (J. Clin. Invest. 1993. 92:1875-1880

Laboratory and clinical Pseudomonas aeruginosa strains do not bind glycosphingolipids in vitro or during type IV pili-mediated initial host cell attachment

“…An accumulation of Gg 4 in CF cells (Bryan et al, 1998;Saiman & Prince, 1993), resulting from hyposialylation (Poschet et al, 2001) due to an altered Golgi pH in CFTR mutant cells, has been questioned (Jiang et al, 1997), but was verified in our work. IB3-1 cells contain at least twice the levels of Gg 4 of S9 cells; intracellular Gg 4 , in structures consistent with Golgi/ER, was observed for both cell types.…”

“…The finding that P. aeruginosa expressing type IV pili belonging to group 1 are significantly overrepresented among isolates from the CF population (Kus et al, 2004) prompted the current study to determine whether differential receptor binding specificity might explain this epidemiological correlation. The binding of T4P in in vitro assays to the glycosphingolipids (GSLs) gangliotriaosylceramide (GalNAcb1-4Galb-4Glc ceramide, Gg 3 ) and gangliotetraosylceramide (Galb1-3GalNAcb1-4Gal b-4Glc ceramide, Gg 4 ) (also commonly termed asialoGM2 and asialoGM1, respectively) (Comolli et al, 1999b;Gupta et al, 1994;Lee et al, 1994;Saiman & Prince, 1993;Schweizer et al, 1998) has implicated these molecules as cellular receptors for adhesion of P. aeruginosa (Baker et al, 1990;Hazlett et al, 1993;Krivan et al, 1988a;Ramphal et al, 1991a). These GSLs contain the common sequence GalNAcb1-4Gal, which has been defined as the minimal T4P recognition epitope or adhesintope (Campbell et al, 1997;Lee et al, 1996).…”

“…Anti-Gg 4 antibodies have been shown to react directly with the bacterium (Schroeder et al, 2001), providing an alternative explanation for earlier findings. Gg 4 has been reported to be increased in cells containing non-functional CFTR (Bryan et al, 1998;Saiman & Prince, 1993) due to reduced sialylation (Poschet et al, 2001), providing an attractive hypothesis for the increased colonization of respiratory epithelium of CF patients.…”

Genetic features of Pseudomonas aeruginosa isolates from cystic fibrosis patients compared with those of isolates from other origins

“…The nature of the protein encoded by this gene in P. aeruginosa PAO1 is unknown (Stover et al, 2000). Several arguments suggest that nan1 encodes a sialidase, an enzyme theoretically able to release sialic acid from sialylated gangliosides, thus increasing the amount of asialoGM1, a major receptor for adherence to the respiratory tract (Bryan et al, 1998;de Bentzmann et al, 1996;Imundo et al, 1995;Saiman et al, 1992;Saiman & Prince, 1993). The first argument is that the deduced bacterial protein encoded by nan1 possesses four Asp-boxes, a characteristic of bacterial sialidases (Taylor, 1996;Vimr, 1994).…”

Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease

“…The link between the mutation and its lethal sequelae is unknown. Recently, there has been some insight from findings indicating that the CFTR mutation is linked to three abnormalities favoring the onset and persistence of Pseudomonas aeruginosa infection in the lung: (i) undersialylated cell surface glycolipids that act as P. aeruginosa-binding sites (2), (ii) impaired capacity for bronchial epithelial cells to clear P. aeruginosa by endocytosis (3), and (iii) decreased activity of bronchial bacteriolytic substances due to abnormal airway surface liquid (4). Clinically, the onset of P. aeruginosa infection in the CF lung presages airway mucus obstruction and an overall deterioration of lung function.…”