Host mucin glycosylation plays a role in bacterial adhesion in lungs of individuals with cystic fibrosis

Abstract

Malfunction of the cell surface glycoprotein, cystic fibrosis transmembrane conductance regulator, is the molecular hallmark of cystic fibrosis (CF), causing salt imbalance across the lung epithelium and biochemical and biophysical alterations of the mucous secretion and airway surfaces. Abnormal glycosylation of both secreted and membrane-tethered airway mucins in CF hosts are reported by a substantial body of literature and correlates with bacterial infection and inflammation in CF airways, features that are linked to the CF pathology. It is established that Pseudomonas aeruginosa and other CF-typic bacteria use the altered host mucin glycosylation as receptors for adhesion by dedicated lectins and adhesins recognizing an array of the aberrantly expressed glycan determinants. This review aims to describe the aberrant mucin glycosylation phenotype observed in CF airways relative to the non-CF equivalent by summarizing the wealth of literature on this topic. The possible causes and effects of altered glycosylation in the respiratory system are discussed. Specific attention is given to the adhesion mechanisms of the opportunistic P. aeruginosa, which utilizes the molecular alterations of the lung to gain access to the normally sterile airways. Finally, the emerging glycosylation-based therapeutics that show promising potential for reducing bacterial infection in individuals with CF by molecular mimicry mechanisms are discussed.

Keywords::

• adhesion
• cystic fibrosis
• glycan
• glycosidase
• infection
• inflammation
• lectin
• lung
• mucin
• mucous
• Pseudomonas aeruginosa
• protein glycosylation
• respiratory system
• sputum

Acknowledgments

This work was supported by an ARC Super Science Fellowship for M Thaysen-Andersen and a Macquarie University Research Excellence Scholarship for V Venkatakrishnan.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Cystic fibrosis (CF) is a genetic disease characterized by the lack of a functional ion transporter, cystic fibrosis transmembrane conductance regulator, which leads to chronic lung inflammation and bacterial infection with subsequent deterioration of the lung function and premature death of individuals with CF.

• • Biophysical and biochemical alterations are observed in CF airway cells and mucous secretions. Aberrant mucin glycosylation of CF sputum and airway cells (compared to non-CF individuals) has been reported repeatedly and certain molecular trends can be extracted from the literature. The quantitative changes in glycosylation, however, are still not accurately defined due to large interexperiment variations caused by significant patient and sample differences as well as analytical inaccuracies.

• • The CF glycosylation phenotype can be divided into changes relating to secreted mucins in sputum and membrane-tethered mucins on airway cells because of the different molecular and cellular origins. The CF glycosylation phenotype can roughly be described as increased sulfation/sialylation in sputum and decreased sialylation/increased fucosylation for membrane-tethered mucins of airway cells compared with non-CF controls. In addition, mucins from both groups showed reduced levels of global glycosylation in CF.

• • It is far from fully understood how the biomolecular alterations are related to the absence of functional CFTR. Specifically, little is known on the causes and effects of the aberrant mucin glycosylation in CF, but convincing evidence correlates these biomolecular changes to increased presence of bacteria and inflammation in the lungs of individuals with CF.

• • CF-typic bacteria including Pseudomonas aeruginosa are capable of recognizing these altered glycan determinants on mucins and glycolipids through lectins/adhesins presented on their surfaces to facilitate their adhesion. P. aeruginosa and other respiratory pathogens can also modify the host glycan environment using bacterial glycosidases presumably to uncover previously unexposed determinants for added binding strength/opportunity.

• • Glyco-centric therapeutics are being designed with the aim of reducing/preventing bacterial infection in CF. Many of these therapeutic candidates act through molecular decoy mechanisms by closely mimicking the glycan receptor environment present on CF airway mucins. Glycopeptide dendrimers represent a novel class of such promising therapeutics that show increased inhibition of bacterial adhesion by mimicking the multivalent glycan receptor environment occurring in the host airways thereby potentially reducing lung infection in CF.

Notes