Molecular features underlying Pseudomonas aeruginosa persistence in human plasma

Abstract

Persistence of bacterial pathogens is a main cause of treatment failure and establishment of chronic bacterial infection. Pseudomonas aeruginosa, an opportunistic Gram-negative pathogen is a leading cause of bacteremia with high associated mortality. In a previous study, we found that plasma-sensitive P. aeruginosa strains were able to form a persister-like sub-population named evaders. However, the molecular mechanisms underlying emergence and biology of evaders remained unknown. Here, using a gain-of-function genetic screen we examined the molecular determinants of persistence in plasma. In addition to known virulence factors (long O-specific antigens and exopolysaccharides), we found that ATP and biotin availability greatly impact bacterial survival in plasma. Mutants in genes of purine and biotin pathways display higher tolerance and persistence, respectively. Moreover, we identified a novel small protein named SrgA whose expression leads to 100-fold increase in survival in plasma. The analysis of different steps of complement activity and the use of outer-membrane impermeable drug nisin suggest that the mutants impede MAC activity per se. Through this work we highlight the multifactorial origin of bacterial resilience to plasma and pave the way to a more comprehensive picture of the complex interplay between P. aeruginosa and the complement system in the blood.