Abstract
Pseudomonas aeruginosa uses a complex type III secretion system to inject the toxins ExoS, ExoT, ExoU, and ExoY into the cytosol of target eukaryotic cells. This system is regulated by the exoenzyme S regulon and includes the transcriptional activator ExsA. Of the four toxins, ExoU is characterized as the major virulence factor responsible for alveolar epithelial injury in patients with P. aeruginosa pneumonia. Virulent strains of P. aeruginosa possess the exoU gene, whereas non-virulent strains lack this particular gene. The mechanism of virulence for the exoU+ genotype relies on the presence of a pathogenic gene cluster (PAPI-2) encoding exoU and its chaperone, spcU. The ExoU toxin has a patatin-like phospholipase domain in its N-terminal, exhibits phospholipase A2 activity, and requires a eukaryotic cell factor for activation. The C-terminal of ExoU has a ubiquitinylation mechanism of activation. This probably induces a structural change in enzymatic active sites required for phospholipase A2 activity. In P. aeruginosa clinical isolates, the exoU+ genotype correlates with a fluoroquinolone resistance phenotype. Additionally, poor clinical outcomes have been observed in patients with pneumonia caused by exoU+-fluoroquinolone-resistant isolates. Therefore, the potential exists to improve clinical outcomes in patients with P. aeruginosa pneumonia by identifying virulent and antimicrobial drug-resistant strains through exoU genotyping or ExoU protein phenotyping or both.
Highlights
Multidrug-resistant (MDR) Pseudomonas aeruginosa has been identified as a major cause of nosocomial infections [1,2]
This review summarizes progress with respect to basic research conducted on the The type III secretory (TTS) toxin, ExoU, to date
P. aeruginosa ExoU, a toxin injected into the cytosol of target eukaryotic cells such as phagocytes and epithelial cells, is a major virulence factor in the cause of alveolar lung injury in patients with P. aeruginosa pneumonia
Summary
Multidrug-resistant (MDR) Pseudomonas aeruginosa has been identified as a major cause of nosocomial infections [1,2]. ExoU as a major virulence factor Isolates of P. aeruginosa show cytotoxicity in cultured epithelial cells and cause a high degree of acute lung injury in animal models of pneumonia [13,14,15]. Cytotoxic clinical isolates secreting ExoU caused severe and acute epithelial injury in animal models of P. aeruginosa pneumonia (Figure 2) [24]. When Schulert and colleagues [74] analyzed the virulence profiles of 35 P. aeruginosa isolates from patients with hospital-acquired pneumonia by using a cytolytic cell-death assay, an apoptosis assay, and a mouse model of pneumonia, they found that increased virulence was associated with the secretion of ExoU but not ExoS or ExoY secretion These studies suggest that P. aeruginosa TTSS is present in most clinical and environmental isolates. More details regarding the activation mechanisms of ExoU have been recently reported; there is more potential in using small chemicals for the prevention of acute lung injury induced by P. aeruginosa
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