Lack of control of Pseudomonas aeruginosa pulmonary infection in the absence of recognition of both lipopolysaccharide and flagellin

Abstract

Introduction Pseudomonas aeruginosa is a major cause of morbidity in cystic fibrosis and a major cause of acute nosocomial infection. Toll-like receptors (TLRs) are important for the recognition of pathogens and the induction of an innate immune response. We previously demonstrated that mice deficient in TLR2 and TLR4 (TLR2,4-/-) were not hypersusceptible to lung infection by a wild- type P aeruginosa strain. We thus hypothesized that the flagellin- TLR5 pathway would play a role in the lung defense against this bacterium. Methodology Wild-type mice (WT) and TLR2,4 deficient mice (TLR2,4-/-) were infected intra-tracheally with a wild-type P aeruginosa strain (PAK) or a mutant devoid of flagellin production. In some experiments luminescent strains were used. Cytokines, polymorphonuclear neutrophils and bacterial loads were measured in broncho-alveolar lavages performed at 6 hours after infection. Results TLR2,4-/- mice are hypersusceptible to infection to P aeruginosa unable to produce flagellin. Infected mice show low amounts of TNF-α, IL-6, KC and G-CSF, do not mobilize neutrophils and fail to control bacterial replication in the lung. By contrast, administration of the same P aeruginosa mutant to wild-type mice triggers a protective innate response comparable to that induced by the wild-type P aeruginosa strain. The intrapulmonary administration of flagellin following infection by the P aeruginosa mutant saved 100% of TLR2,4-/- mice from death. Conclusions We demonstrated that hypersusceptibility is due to the combined effects of the TLR4 mutation and the absence of flagellin in the bacterium implicating TLR5. We conclude that either TLR4 or TLR5 can effectively defend the lung from P aeruginosa infection.