ROLE OF FLAGELLA IN PATHOGENESIS OF PSEUDOMONAS-AERUGINOSA PULMONARY INFECTION

Pseudomonas aeruginosa strains are opportunistic pathogens associated with infections in immunocompromised hosts and patients with cystic fi brosis, Like many other mucosal pathogens, P. aeruginosa cells express flagella which provide motility and chemotaxis toward preferred subst rates but also provide a ligand for clearance by phagocytic cells. We tested the role of flagella in the initial stages of respiratory tract infection by comparing the virulence of fliC mutants in a neonatal mo use model of pneumonia. In the absence of fliC, there was no mortality , compared with 30% mortality attributed to the parental strain PAK or 15% mortality associated with infection due to a pilA mutant PAK/NP ( P < 0.0001). The fliC mutants caused pneumonia in only 25% of the mice inoculated, regardless of whether there was expression of the pilus, whereas the parental strain was associated with an 80% rate of pneumon ia. Histopathological studies demonstrated that the fliC mutants cause d very focal inflammation and that the organisms did not spread throug h the lungs as seen in infection due to either PAK or PAK/NP. Purified flagellin elicited an intense inflammatory response in the mouse lung . I-125-labeled flagellin bound to the glycolipids GM1 and GD(1a) and to asialoGM1 in an in vitro binding assay. However, flagellin-mediated binding to epithelial gangliosides was a relatively unusual event, as quantified by binding assays of wild-type or fliC mutant organisms to CHO Lec-2 cells with membrane-incorporated GM1. Fla(+) organisms but not fliC mutants were efficiently taken up by murine macrophages. P. a eruginosa flagella are important in the establishment of respiratory t ract infection and may act as a tether in initial interactions with ep ithelial membranes. This function is offset by the contribution of fla gella to host clearance mechanisms facilitating phagocytic clearance a nd the role of flagellar genes in mucin binding and clearance.