A remarkable zinc acquisition ability contributes to Pseudomonas aeruginosa ability to express virulence features and infect the lung of human patients

The immune response to microbial pathogens involves numerous strategies aimed at limiting the access of microorganisms to transition metals that are essential for the activity of a large number of bacterial proteins. Metal shortage may be particularly acute in the inflamed airway mucosa of Cystic Fibrosis (CF) patients, where neutrophils release large amounts of the antimicrobial protein Calprotectin that is able to control microbial growth by the sequestration of zinc ions. Pseudomonas aeruginosa, one of the most dangerous pathogens for patients with Cystic Fibrosis, possesses redundant zinc uptake systems that facilitate metal recruitment in environments poor of this metal. We have shown that an adequate supply of zinc is essential for P. aeruginosa ability to express a large number of virulence traits. Virulence features affected by zinc availability include the ability to release different extracellular proteases, the capability to produce flagella, the ability to synthesize alginate and form biofilm and even the capacity to synthesize the siderophore pyoverdine. In agreement with the importance of zinc in the expression of so many virulence-related features, disruption of the most efficient zinc uptake systems severely affects P. aeruginosa ability to cause acute lung and systemic infections in mice. To verify the importance of zinc uptake systems for the capacity of P. aeruginosa to establish infections in human patients, we have examined the expression of various genes regulated by zinc deficiency in bacteria in the sputum of patients with chronic inflammatory lung diseases. In all the analyzed sputum samples these genes were found to be expressed at levels much higher than those observed in bacteria growing in a Zn-rich medium. This finding supports the hypothesis that P. aeruginosa is under zinc starvation during lung infections. This conclusion is also in agreement with the observation that genes for the major zinc importers are well conserved in the vast majority of clinical isolates from CF patients. The indispensability of zinc makes the homeostasis of this metal an extremely promising target for the development of new antimicrobial therapies aimed at controlling P. aeruginosa pulmonary infections