Abstract
Reactive oxygen species (ROS) are small oxygen-derived molecules that are used to control infections by phagocytic cells. In macrophages, the oxidative burst produced by the NOX2 NADPH-oxidase is essential to eradicate engulfed pathogens by both oxidative and non-oxidative killing. Indeed, while the superoxide anion () produced by NOX2, and the other ROS derived from its transformation, can directly target pathogens, ROS also contribute to activation of non-oxidative microbicidal effectors. The response of pathogens to the phagocytic oxidative burst includes the expression of different enzymes that target ROS to reduce their toxicity. Superoxide dismutases (SODs) are the primary scavengers of , which is transformed into H2O2. In the Gram-negative Salmonella typhimurium, periplasmic SODCI has a major role in bacterial resistance to NOX-mediated oxidative stress. In Pseudomonas aeruginosa, the two periplasmic SODs, SODB, and SODM, appear to contribute to bacterial virulence in small-animal models. Furthermore, NOX2 oxidative stress is essential to restrict P. aeruginosa survival in macrophages early after infection. Here, we focused on the role of P. aeruginosa SODs in the counteracting of the lethal effects of the macrophage oxidative burst. Through this study of the survival of sod mutants in macrophages and the measurement of ROS in infected macrophages, we have identified a dual, antagonistic, role for SODB in P. aeruginosa survival. Indeed, the survival of the sodB mutants, but not of the sodM mutants, was greater than that of the wild-type (WT) bacteria early after infection, and sodB-infected macrophages showed higher levels of and lower levels of H2O2. This suggests that SODB contributes to the production of lethal doses of H2O2 within the phagosome. However, later on following infection, the sodB mutants survived less that the WT bacteria, which highlights the pro-survival role of SODB. We have explained this defensive role through an investigation of the activation of autophagy, which was greater in the sodB-infected macrophages.
Highlights
Macrophages are professional phagocytes, and their major role in the control of infectious diseases is the engulfment of microorganisms within phagosomes, which in a complex maturation process acquire disparate microbicidal effectors (Flannagan et al, 2009, 2012)
We have shown that macrophages infected with PAO1 sodB are differentiated by increased levels of O−2 and lower levels of H2O2, with respect to those infected with PAO1 WT
This turns out to have a negative impact on bacterial survival within the macrophages, as we found that the short-term survival of the PAO1 sodB mutant was greater than that of PAO1 WT
Summary
Macrophages are professional phagocytes, and their major role in the control of infectious diseases is the engulfment of microorganisms within phagosomes, which in a complex maturation process acquire disparate microbicidal effectors (Flannagan et al, 2009, 2012). Following the engulfment of pathogens by macrophages, the NOX2 multisubunit complex is assembled and activated at the phagosome membrane, where it liberates superoxide anions, O−2 , into the phagosomal lumen (Lam et al, 2010). Myeloperoxidase targets H2O2 to produce hypochlorous acid, which has potent microbicidal activity (Fang, 2011). Pathogens enclosed within phagosomes are exposed to high levels of ROS, which are produced in their close proximity, and which can directly kill the engulfed bacteria by targeting different microbial macromolecules, such as their DNA and proteins, and in particular, iron–sulfur-clustered protein (Fang, 2011). The survival of pathogens in this environment is critically dependent on their detoxification of ROS in the early stages of an infection
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