Mutation of Pseudomonas aeruginosa lasI/rhlI diminishes its cytotoxicity, oxidative stress, inflammation, and apoptosis on THP-1 macrophages

The management of Pseudomonas aeruginosa (P. aeruginosa) infections presents a substantial challenge to clinics and public health, emphasizing the urgent need for innovative strategies to address this issue. Quorum sensing (QS) is an intercellular communication mechanism that coordinates bacterial activities involved in various virulence mechanisms, such as acquiring host nutrients, facilitating biofilm formation, enhancing motility, secreting virulence factors, and evading host immune responses, all of which play a crucial role in the colonization and infection of P. aeruginosa. The LasI/R and RhlI/R sub-systems dominate in the QS system of P. aeruginosa. Macrophages play a pivotal role in the host's innate immune response to P. aeruginosa invasion, particularly through phagocytosis as the initial host defense mechanism. This study investigated the effects of P. aeruginosa's QS system on THP-1 macrophages. Mutants of PAO1 with lasI/rhlI deletion, as well as their corresponding complemented strains, were obtained, and significant downregulation of QS-related genes was observed in the mutants. Furthermore, the Delta lasI and Delta lasI Delta rhlI mutants exhibited significantly attenuated virulence in terms of biofilm formation, extracellular polymeric substances synthesis, bacterial adhesion, motility, and virulence factors production. When infected with Delta lasI and Delta lasI Delta rhlI mutants, THP-1 macrophages exhibited enhanced scavenging ability against the mutants and demonstrated resistance to cytotoxicity, oxidative stress, inflammatory response, and apoptosis induced by the culture supernatants of these mutant strains. These findings offer novel insights into the mechanisms underlying how the lasI/rhlI mutation attenuates cytotoxicity, oxidative stress, inflammation, and apoptosis in macrophages induced by P. aeruginosa.