Abstract
Alpha-toxin (Hla) is a major virulence factor of Staphylococcus aureus (S. aureus) and plays an important role in S. aureus-induced pneumonia. It binds as a monomer to the cell surface of eukaryotic host cells and forms heptameric transmembrane pores. Sensitivities toward the toxin of various types of potential host cells have been shown to vary substantially, and the reasons for these differences are unclear. We used three human model airway epithelial cell lines (16HBE14o-, S9, A549) to correlate cell sensitivity (measured as rate of paracellular gap formation in the cell layers) with Hla monomer binding, presence of the potential Hla receptors ADAM10 or α5β1 integrin, presence of the toxin-stabilizing factor caveolin-1 as well as plasma membrane lipid composition (phosphatidylserine/choline, sphingomyelin). The abundance of ADAM10 correlated best with gap formation or cell sensitivities, respectively, when the three cell types were compared. Caveolin-1 or α5β1 integrin did not correlate with toxin sensitivity. The relative abundance of sphingomyelin in plasma membranes may also be used as a proxi for cellular sensitivity against alpha-toxin as sphingomyelin abundances correlated well with the intensities of alpha-toxin mediated gap formation in the cell layers.
Highlights
The human respiratory epithelium and its luminal mucus layer constitute the barrier between the airspace and the interior of the body [1]
The monomeric alpha-toxin of S. aureus seems to bind with preference to ADAM10 associated with the outer leaflets of plasma membranes of many mammalian cells including human fibroblasts and epithelial cells [12, 13, 41, 42]
The amount of receptor molecules on a given cell may determine the number of toxin molecules that simultaneously bind to the cell surface when the toxin concentration in the extracellular space is sufficiently high with respect to the affinity of the cell surface receptor
Summary
The human respiratory epithelium and its luminal mucus layer constitute the barrier between the airspace and the interior of the body [1]. Salt and water which results in formation of the airway surface liquid (ASL). It consists of two layers, a thin 8 μm) periciliary liquid layer (PCL) of low viscosity in which the cilia of the ciliated cells of the airway epithelium beat, and a thicker mucus layer (up to 50 μm) above the PCL that is highly viscous and serves to trap inhaled dust particles and pathogens [2]. By the beating of the cilia the mucus layer including the adherent particles is transported towards the pharynx. Determinants for host cell sensitivity toward S. aureus alpha-toxin heptamerization ebi.ac.uk/biostudies/) under the accession number S-BSST397
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