Abstract
BackgroundLower respiratory infections are among the top ten causes of death worldwide. Since pathogen to cell adhesion is a crucial step in the infection progress, blocking the interaction between eukaryotic receptors and bacterial ligands may enable the pathogenesis process to be stopped. Cell surface glycosaminoglycans (GAGs) are known to be mediators in the adhesion of diverse bacteria to different cell types, making it of interest to examine their involvement in the attachment of various pathogenic bacteria to lung cells, including epithelial cells and fibroblasts.MethodsThe function of cell surface GAGs in bacterial adhesion was studied by reducing their levels through inhibiting their biosynthesis and enzymatic degradation, as well as in binding competition experiments with various species of GAGs. The participation of the different bacterial adhesins in attachment was evaluated through competition with two peptides, both containing consensus heparin binding sequences. Blocking inhibition assays using anti-syndecans and the enzymatic removal of glypicans were conducted to test their involvement in bacterial adhesion. The importance of the fine structure of GAGs in the interaction with pathogens was investigated in competition experiments with specifically desulfated heparins.ResultsThe binding of all bacteria tested decreased when GAG levels in cell surface of both lung cells were diminished. Competition experiments with different types of GAGs showed that heparan sulfate chains are the main species involved. Blocking or removal of cell surface proteoglycans evidenced that syndecans play a more important role than glypicans. The binding was partially inhibited by peptides including heparin binding sequences. Desulfated heparins also reduced bacterial adhesion to different extents depending on the bacterium and the sulfated residue, especially in fibroblast cells.ConclusionsTaken together, these data demonstrate that the GAG chains of the cell surface are involved in the adhesion of bacterial adhesins to lung cells. Heparan sulfate seems to be the main species implicated, and binding is dependent on the sulfation pattern of the molecule. These data could facilitate the development of new anti-infective strategies, enabling the development of new procedures for blocking the interaction between pathogens and lung cells more effectively.
Highlights
Lower respiratory infections are among the top ten causes of death worldwide
GAGs are involved in the adherence of pathogenic bacteria to lung cells To analyze the possible involvement of GAGs in the adhesion of some common lung pathogens, biosynthesis inhibition experiments were performed in both lung fibroblasts and epithelial cells using two different compounds that disrupt synthesis at different levels, rhodamine B or genistein [32,33,34,35]
The cells treated with the inhibitors were exposed to previously labeled pathogens in individual experiments, resulting in a decrease in bacterial adherence in all cases, suggesting that GAGs are involved in the binding of the pathogens in both types of cell (Fig. 1a, b)
Summary
Lower respiratory infections are among the top ten causes of death worldwide. Infectious pathologies remain an important health problem, being among the 10 leading causes of death worldwide [1]. In addition to the infectious diseases not yet eradicated, emerging and re-emerging infections may appear. This is frequently due to multiple factors including environmental changes, lack of prevention measures, travel and global trade, alterations in host susceptibility and, adaptive genetic changes in the microorganisms themselves [2]. Of the myriad communicable pathologies currently affecting humankind, the World Health Organization has highlighted the threat from lower respiratory infections and tuberculosis, both of which continue to be among the global top ten causes of death [1]. Infections of the lower respiratory tract are caused by a variety of pathogens including viruses and fungi, bacteria are the main causative agents [5]
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