Association between Pseudomonas aeruginosa type III secretion, antibiotic resistance, and clinical outcome: a review

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.

Type I CRISPR-Cas targets endogenous genes and regulates virulence to evade mammalian host immunity

“…However, transcript levels of algC were similar between these two PA14 strains (Supplementary information, Figure S2A). We then assessed transcript levels of several virulence factors and virulence-associated factors that are known to be injected via the type 3 secretion system (T3SS) into host cells to facilitate invasion [16,17]. We found that mRNA levels of T3SS exoenzymes ExoT, ExoU and ExoY and virulence-associated factors LasR, LasI, RhlR, RhlI and RpoS were all significantly increased in PA14 ∆TCR mutant compared with those in WT strain, and the increase was reversed in the ∆TCR strain complemented with CRISPR-Cas system (named the complemented strain hereafter; Figure 1B and Supplementary information, Figure S2A).…”

The prophylactic effects of human IgG derived from sera containing high anti-PcrV titers against pneumonia-causingPseudomonas aeruginosa

“…[3][4][5] P. aeruginosa clinical isolates are often resistant to most b-lactams and fluoroquinolones and, sometimes, resistant to aminoglycosides, such as gentamicin and amikacin, thus categorizing them as multi-drug resistant P. aeruginosa (MDRP). 4,[6][7][8][9] Limitations in the number of effective antimicrobial agents for treating MDRP infections leads to the high mortality rates associated with the acute lung injury induced by this bacterium. 5 While seeking new prophylactic or therapeutic strategies that do not rely on conventional antimicrobial agents, we have investigated the use of an immunotherapy approach that targets the P. aeruginosa type III secretion system.…”

Detection of Exotoxins and Antimicrobial Susceptibility Pattern in Clinical Pseudomonas Aeruginosa Isolates

“…The existence many of agents in P. aeruginosa leads to intrinsic resistance to many antimicrobials including bacterium's outer membrane barrier, the presence of multi drug efflux trans-porters and endogenous antimicrobial inactivation. The all of this agents, also inappropriate chemotherapy and lagging in antibiotic discovery was caused "antibiotic resistance crisis" (6,9). The previous studies were showed that the inappropriate chemotherapy leads to emerge of the multi-drug resistant isolates (10), especially in burn patients, the rate of resistance to most of antibiotics for P. aeruginosa isolated was reported higher than 70% (11), However, the ExoU + isolates are more resistance to floroquinolons (12).…”

“…The type III secretion system (TTSS) has been known to be a major virulence, which is determined in pathogenesis of acute infection, bacteremia, sepsis and subsequent mortality. The TTSS allows the injection of toxins into the cytosol of target eukaryotic cells, where they destroy host cell defense and signaling systems and that subsequently rapid call necrosis or modulating the actin cytoskeleton (4)(5)(6). Four effector proteins have been identified: ExoU, which is a phospholipase and it has been characterized as a major virulence factor in acute lung injury, ExoY that is an adenylate cyclase, and ExoS and ExoT which are bifunctional proteins (5,6).…”

“…The TTSS allows the injection of toxins into the cytosol of target eukaryotic cells, where they destroy host cell defense and signaling systems and that subsequently rapid call necrosis or modulating the actin cytoskeleton (4)(5)(6). Four effector proteins have been identified: ExoU, which is a phospholipase and it has been characterized as a major virulence factor in acute lung injury, ExoY that is an adenylate cyclase, and ExoS and ExoT which are bifunctional proteins (5,6). ExoU and ExoS are present variably and in pathogenesis are important, whereas the almost of isolates, ExoT and ExoY encode and have a minor effect on virulence (4,5).…”