Abstract
BackgroundIt has been recently reported that major pathogens Staphylococcus aureus and Pseudomonas aeruginosa accelerate a normal process of cell surface syndecan-1 (Synd1) ectodomain shedding as a mechanism of host damage due to the production of shedding-inducing virulence factors. We tested if acceleration of Synd1 shedding takes place in vitro upon treatment of epithelial cells with B. anthracis hemolysins, as well as in vivo during anthrax infection in mice.ResultsThe isolated anthrax hemolytic proteins AnlB (sphingomyelinase) and AnlO (cholesterol-binding pore-forming factor), as well as ClnA (B. cereus homolog of B. anthracis phosphatidyl choline-preferring phospholipase C) cause accelerated shedding of Synd1 and E-cadherin from epithelial cells and compromise epithelial barrier integrity within a few hours. In comparison with hemolysins in a similar range of concentrations, anthrax lethal toxin (LT) also accelerates shedding albeit at slower rate. Individual components of LT, lethal factor and protective antigen are inactive with regard to shedding. Inhibition experiments favor a hypothesis that activities of tested bacterial shedding inducers converge on the stimulation of cytoplasmic tyrosine kinases of the Syk family, ultimately leading to activation of cellular sheddase. Both LT and AnlO modulate ERK1/2 and p38 MAPK signaling pathways, while JNK pathway seems to be irrelevant to accelerated shedding. Accelerated shedding of Synd1 also takes place in DBA/2 mice challenged with Bacillus anthracis (Sterne) spores. Elevated levels of shed ectodomain are readily detectable in circulation after 24 h.ConclusionThe concerted acceleration of shedding by several virulence factors could represent a new pathogenic mechanism contributing to disruption of epithelial or endothelial integrity, hemorrhage, edema and abnormal cell signaling during anthrax infection.
Highlights
It has been recently reported that major pathogens Staphylococcus aureus and Pseudomonas aeruginosa accelerate a normal process of cell surface syndecan-1 (Synd1) ectodomain shedding as a mechanism of host damage due to the production of shedding-inducing virulence factors
We found that lethal toxin (LT) stimulates Synd1 shedding by the mechanism which involves the mitogen-activated protein kinase kinases (MAPKK) signaling pathways
We suggest that a cumulative effect of several virulence factors on ectodomain shedding could compromise the integrity of host protective barriers, cause malfunction of major organs, and contribute to the pathological systemic response typical in anthrax patients
Summary
It has been recently reported that major pathogens Staphylococcus aureus and Pseudomonas aeruginosa accelerate a normal process of cell surface syndecan-1 (Synd1) ectodomain shedding as a mechanism of host damage due to the production of shedding-inducing virulence factors. It has been recently reported that major pathogens Staphylococcus aureus and Pseudomonas aeruginosa exploit acceleration of syndecan (Synd) ectodomain shedding as a mechanism of host damage and increase their virulence [1,2,3]. The diverse list of proteins, which are normally shed from the cell surface includes but is not limited to cytokines, growth factors, and cell adhesion molecules, such as tumor necrosis factor (TNFα), transforming growth factor α (TGFα), epidermal growth factors (EGFs), L-selectin, CD44, and Synds [[5] and citations within]. Syndecans act as adhesion molecules, modulators of growth factor function, and coreceptors in processes as diverse as morphogenesis, tissue repair, host defense, tumor development, and energy metabolism. A growing body of evidence indicates that these molecular and cellular features enable ectodomain shedding to regulate many pathophysiological processes, such as microbial pathogenesis, inflammation, and tissue repair [1,8]
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