Abstract
The opportunistic pathogen Pseudomonas aeruginosa causes a wide range of infections in multiple hosts by releasing an arsenal of virulence factors such as pyocyanin. Despite numerous reports on the pleiotropic cellular targets of pyocyanin toxicity in vivo, its impact on erythrocytes remains elusive. Erythrocytes undergo an apoptosis‐like cell death called eryptosis which is characterized by cell shrinkage and phosphatidylserine (PS) externalization; this process confers a procoagulant phenotype on erythrocytes as well as fosters their phagocytosis and subsequent clearance from the circulation. Herein, we demonstrate that P. aeruginosa pyocyanin‐elicited PS exposure and cell shrinkage in erythrocyte while preserving the membrane integrity. Mechanistically, exposure of erythrocytes to pyocyanin showed increased cytosolic Ca2+ activity as well as Ca2+‐dependent proteolytic processing of μ‐calpain. Pyocyanin further up‐regulated erythrocyte ceramide abundance and triggered the production of reactive oxygen species. Pyocyanin‐induced increased PS externalization in erythrocytes translated into enhanced prothrombin activation and fibrin generation in plasma. As judged by carboxyfluorescein succinimidyl‐ester labelling, pyocyanin‐treated erythrocytes were cleared faster from the murine circulation as compared to untreated erythrocytes. Furthermore, erythrocytes incubated in plasma from patients with P. aeruginosa sepsis showed increased PS exposure as compared to erythrocytes incubated in plasma from healthy donors. In conclusion, the present study discloses the eryptosis‐inducing effect of the virulence factor pyocyanin, thereby shedding light on a potentially important mechanism in the systemic complications of P. aeruginosa infection.
Highlights
The opportunistic pathogen Pseudomonas aeruginosa causes a wide range of infections in humans and is responsible for the progressive loss of pulmonary function in patients with cystic fibrosis [1, 2]
We further tested whether other P. aeruginosa phenazine derivatives such as 1hydroxyphenazine and phenazine-1-carboxylic acid induced erythrocyte PS exposure
This study unravels the, hitherto unknown, effect of P. aeruginosa pyocyanin on erythrocytes i.e. the stimulation of phospholipid cell membrane scrambling and cell shrinkage accompanied by enhanced cytosolic Ca2+ activity, ceramide formation and Reactive Oxygen Species (ROS) generation
Summary
The opportunistic pathogen Pseudomonas aeruginosa causes a wide range of infections in humans and is responsible for the progressive loss of pulmonary function in patients with cystic fibrosis [1, 2]. P. aeruginosa is a primary cause of sepsis and mortality in immunocompromised individuals [3, 4]. It can infect hosts of multiple phylogenetic backgrounds and has a complex pathophysiology of infection because of the release of a large arsenal of virulence factors [5]. Toxic metabolites produced by P. aeruginosa include alkaline proteases, elastase, rhamnolipids and phenazines [2, 6, 7]. Pyocyanin (N-methyl-1-hydroxyphenazine), a redox-active secondary metabolite, is toxic for both eukaryotic and prokaryotic cells and is a major virulence factor in P. aeruginosa infection in humans [9,10,11]
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