Abstract
Pseudomonas aeruginosa is a multidrug-resistant, opportunistic pathogen that utilizes a wide-range of virulence factors to cause acute, life-threatening infections in immunocompromised patients, especially those in intensive care units. It also causes debilitating chronic infections that shorten lives and worsen the quality of life for cystic fibrosis patients. One of the key virulence factors in P. aeruginosa is the siderophore pyoverdine, which provides the pathogen with iron during infection, regulates the production of secreted toxins, and disrupts host iron and mitochondrial homeostasis. These roles have been characterized in model organisms such as Caenorhabditis elegans and mice. However, an intermediary system, using cell culture to investigate the activity of this siderophore has been absent. In this report, we describe such a system, using murine macrophages treated with pyoverdine. We demonstrate that pyoverdine-rich filtrates from P. aeruginosa exhibit substantial cytotoxicity, and that the inhibition of pyoverdine production (genetic or chemical) is sufficient to mitigate virulence. Furthermore, consistent with previous observations made in C. elegans, pyoverdine translocates into cells and disrupts host mitochondrial homeostasis. Most importantly, we observe a strong correlation between pyoverdine production and virulence in P. aeruginosa clinical isolates, confirming pyoverdine’s value as a promising target for therapeutic intervention. This in vitro cell culture model will allow rapid validation of pyoverdine antivirulents in a simple but physiologically relevant manner.
Highlights
Pseudomonas aeruginosa is a Gram-negative, multidrug-resistant, nosocomial pathogen that frequently causes ventilator-associated pneumonia in intensive care units and chronic lung infections in cystic fibrosis patients [1,2]
Pyoverdine production promotes P. aeruginosa biofilm formation [12], which is consistent with the established paradigm that iron availability is necessary for biofilm development [12,13]
We demonstrate that pyoverdine translocates into macrophages and disrupts mitochondrial homeostasis, consistent with our previous observations in C. elegans
Summary
Pseudomonas aeruginosa is a Gram-negative, multidrug-resistant, nosocomial pathogen that frequently causes ventilator-associated pneumonia in intensive care units and chronic lung infections in cystic fibrosis patients [1,2]. This pathogen has a diverse set of virulence determinants that facilitate host infection, including those that enable it to avoid immune recognition (e.g., elastases) [3,4] and obtain nutrients within the host (e.g., siderophores, proteases, lipases, etc.) [5]. Pyoverdine production promotes P. aeruginosa biofilm formation [12], which is consistent with the established paradigm that iron availability is necessary for biofilm development [12,13]
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