Strain-Specific Variation in the Complement Resistome of Pseudomonas aeruginosa

Bloodstream infections caused by Pseudomonas aeruginosa are associated with the highest mortality rates. The complement system, key component of the innate immune response, is mostly responsible for P. aeruginosa elimination in human blood. Nevertheless, the plasma sensitivity of P. aeruginosa strains varies, ranging from highly sensitive, persistent to fully resistant. Whereas most studies rely on model strains, given the species high genomic and phenotypic diversity, the interaction between P. aeruginosa and the complement system may be highly complex. In this work, we characterized the plasma resistome of P. aeruginosa in three strains displaying variable plasma sensitivity using Tn-seq. The gain-of-function screen performed on the sensitive strain PA14 highlighted numerous bacterial factors impacting plasma resistance, including members of the RetS-LadS/Gac/Rsm regulatory system and outer membrane porins. Tn-seq in plasma-resistant strains CHA and YIK, suggested that each strain utilizes a specific and limited set of proteins to evade complement-dependent killing. Despite this strain-specific response, we identified common strategies across all strains, including the production of exopolysaccharides (EPSs), the presence of surface appendages and modification in the O-specific antigen. We evidence Ssg and Crc as common factors contributing to plasma resistance. However, whereas mutants lacking ssg and/or crc in plasma had reduced survival, a subpopulation of these mutants persisted over prolonged exposure to human plasma. Overall, this work provides valuable insights into the complex interplay between P. aeruginosa and the complement system in the context of bloodstream infections and raises concerns for the development of therapies targeting individual virulence factors.