Abstract
The effector protein Exotoxin Y (ExoY) produced by Pseudomonas aeruginosa is injected via the type III secretion system (T3SS) into host cells. ExoY acts as nucleotidyl cyclase promoting the intracellular accumulation of cyclic nucleotides. To what extent nucleotidyl cyclase activity contributes to the pathogenicity of ExoY and which mechanisms participate in the manifestation of lung infection is still unclear. Here, we used an acute airway infection model in mice to address the role of ExoY in lung infection. In infected lungs, a dose-dependent phenotype of infection with bacteria-expressing ExoY was mirrored by haemorrhage, formation of interstitial oedema in alveolar septa, and infiltration of the perivascular space with erythrocytes and neutrophilic granulocytes. Analyses of the infection process on the cellular and organismal level comparing infections with Pseudomonas aeruginosa mutants expressing either nucleotidyl cyclase-active or -inactive ExoY revealed differential cytokine secretion, increased prevalence of apoptosis, and a break of lung barrier integrity in mice infected with cyclase-active ExoY. Notably, of all measured cyclic nucleotides, only the increase of cyclic UMP in infected mouse lungs coincides temporally with the observed early pathologic changes. In summary, our results suggest that the nucleotidyl cyclase activity of ExoY can contribute to P. aeruginosa acute pathogenicity.
Highlights
The Gram-negative bacterium Pseudomonas aeruginosa (P. aeruginosa) is an important opportunistic pathogen that preferentially infects patients suffering from a compromisedh immune status or a chronic lung disease [1,2,3,4,5]
As P. aeruginosa has a broad variety of virulence factors and is able to establish biofilm-protected niches, elimination of the bacterium is a central medical concern restricted to chronically ill patients [6,7]
We compared the time course of infection in mice inoculated with Exotoxin Y (ExoY) to that in mice infected with the cyclase-inactive mutant ExoYK81M
Summary
The Gram-negative bacterium Pseudomonas aeruginosa (P. aeruginosa) is an important opportunistic pathogen that preferentially infects patients suffering from a compromisedh immune status or a chronic lung disease [1,2,3,4,5]. One of the bacterial virulence factors is the type III secretion system (T3SS), which enables the bacterium to inject the associated effector proteins ExoS, ExoT, ExoU, and ExoY into eukaryotic host cells via a needle-like structure [8]. These effector proteins affect different intracellular signal transduction pathways resulting in cellular dysfunction and, in cellular death [9]. Several studies with genetically-engineered Pseudomonas mutants lacking genomically-encoded T3SS effectors, but expressing a plasmid-encoded ExoY [10], have been published [15,16,17] In these studies, a distinct phenotype after infection with the mutants could be demonstrated. A closer look at the literature reveals that all studies which have shown distinct in vivo effects of ExoY have been performed using these genetically-constructed Pseudomonas mutants
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