Molecular features underlying Pseudomonas aeruginosa persistence in human plasma

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Abstract
Pseudomonas aeruginosa , an opportunistic Gram-negative pathogen, is a leading cause of bacteremia with a high mortality rate. We recently reported that P. aeruginosa forms a persister-like sub-population of evaders in human plasma and blood. However, the molecular mechanisms underlying the formation of evaders remained unknown. Here, using a gain-of-function genetic screen, we examined the molecular determinants of P. aeruginosa persistence in plasma. We found that, among other factors, ATP and biotin availability greatly influence bacterial survival in plasma; mutants in pur and bio genes display higher tolerance and persistence, respectively. Electron microscopy combined with energy-dispersive X-ray spectroscopy (EDX) revealed the formation of polyphosphate granules upon incubation in plasma in several clinical strains, implying the bacterial response to a low-energy stress signal. Indeed, mutants with transposon insertions in ppk genes were eliminated in the plasma. Analysis of several steps of the complement cascade and exposure to an outer-membrane-impermeable drug, nisin, suggested that the mutants impede membrane attack complex (MAC) activity per se . Through this study, we shed light on P. aeruginosa response to the plasma conditions and discovered the multifactorial origin of bacterial resilience to MAC that provides a comprehensive picture of the complex interplay between P. aeruginosa and the human complement system. Author summary: Persistence of bacterial pathogens is a main cause of treatment failure and establishment of chronic bacterial infection. Despite innate immune responses, some bacteria may persist in human blood and plasma. Here we used a genome-wide screen to investigate the molecular determinants influencing Pseudomonas aeruginosa persistence in human plasma facing the complement system. Alongside a multifactorial strategy, we found intracellular levels of ATP and biotin to significantly influence bacterial capacity to deal with membrane attack complex (MAC)-dependent killing. These results underline the need to understand the complex interplay between bacterial pathogens and the human immune system when seeking to develop efficient antibacterial strategies.
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