Neutrophil extracellular traps exhibit no bactericidal activity against Pseudomonas aeruginosa (P1255)

Abstract

Abstract In CF lungs, PMN are the dominant cell responding to bacterial infection in the lungs. However, PMNs are incapable of preventing chronic colonization and contribute to host damage by excessive release of granule contents and formation of neutrophil extracellular traps (NETs) predominantly composed of DNA. It is currently unclear whether NETs serve to trap bacterial pathogens and, hence, facilitate bacterial colonization, or whether they have weak bactericidal activities. We investigated the kinetics, composition, and functional consequences of NET release in response to Pseudomonas aeruginosa, the most frequent bacterial colonizer of Cystic Fibrosis patients. We found that both non-mucoid and mucoid strains of P. aeruginosa were not sensitive to NET-mediated killing. This was not due to the inability of P. aeruginosa to induce NET formation by PMNs as NETs, released in response to P. aeruginosa, exhibited the typical NET composition. Overstimulation of NET release by PMA treatment prior to infection also failed to reduce the ability of P. aeruginosa to survive. Importantly, the presence of NETs hindered the bactericidal activity of complement. These findings suggest that targeting NETosis could provide an effective therapy for CF. To this end, we identified a host factor, termed, macrophage migration inhibitory factor, which facilitated PMN’s ability to NETose. Therefore, inhibiting MIF in this setting may be a significant innovation in therapy of CF lung disease.