Paraoxonases-2 and -3 Are Important Defense Enzymes against Pseudomonas aeruginosa Virulence Factors due to Their Anti-Oxidative and Anti-Inflammatory Properties
The pathogen Pseudomonas aeruginosa causes serious damage in immunocompromised patients by secretion of various virulence factors, among them the quorum sensing N-(3-oxododecanoyl)-L-homoserine lactone (3OC12) and the redox-active pyocyanin (PCN). Paraoxonase-2 (PON2) may protect against P. aeruginosa infections, as it efficiently inactivates 3OC12 and diminishes PCN-induced oxidative stress. This defense could be circumvented because 3OC12 mediates intracellular Ca2+-rise in host cells, which causes rapid inactivation and degradation of PON2. Importantly, we recently found that the PON2 paralogue PON3 prevents mitochondrial radical formation. Here we investigated its role as additional potential defense mechanism against P. aeruginosa infections. Our studies demonstrate that PON3 diminished PCN-induced oxidative stress. Moreover, it showed clear anti-inflammatory potential by protecting against NF-κB activation and IL-8 release. The latter similarly applied to PON2. Furthermore, we observed a Ca2+-mediated inactivation and degradation of PON3, again in accordance with previous findings for PON2. Our results suggest that the anti-oxidative and anti-inflammatory functions of PON2 and PON3 are an important part of our innate defense system against P. aeruginosa infections. Furthermore, we conclude that P. aeruginosa circumvents PON3 protection by the same pathway as for PON2. This may help identifying underlying mechanisms in order to sustain the protection afforded by these enzymes. 1. Introduction The bacterium Pseudomonas aeruginosa is an opportunistic nosocomial pathogen, which infects the pulmonary tract of, for example, immunocompromised patients or those suffering from cystic fibrosis, pneumonia, burn wounds, HIV, or cancer chemotherapy [1]. The infection causes serious damage in the host, complicated by an often hindered antibiotic treatment due to multiresistances and biofilm formation that provides physical protection. Furthermore, P. aeruginosa secrets a variety of virulence factors to regulate bacterial communication and weaken the defense mechanisms of the infected host. Two important factors are the quorum sensing signal N-(3-oxododecanoyl)-L-homoserine lactone (3OC12) and the redox-active pyocyanin (PCN). 3OC12 is a mediator of the cell-density-dependent signaling system known as quorum sensing, by which the bacteria coordinate their gene expression. If bacterial density and 3OC12 concentration exceed a certain threshold, the bacteria become virulent by expression of virulence factors (immunogenic exoenzymes and toxins) and by inducing
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