Impairment of host defence by exotoxin A in Pseudomonas aeruginosa pneumonia in mice

Exotoxin A (P-ExA) is considered to be a major virulence factor of Pseudomonas aeruginosa. Neutrophils, cytokines and nitric oxide (NO) have been implicated as important components of an effective host defence against bacterial respiratory tract infection. To study the role of P-ExA in the pathogenesis of P. aeruginosa pneumonia, C57Bl/6 mice were inoculated intranasally with wild-type PA103 or a mutant P. aeruginosa strain that did not produce P-ExA, PA103-29. P-ExA facilitated the outgrowth of P. aeruginosa in lungs, as reflected by an increasing number of cfu during pneumonia with strain PA103, whereas the number of cfu decreased during pulmonary infection with strain PA103-29. Influx of neutrophils was similar in broncho-alveolar lavage fluids (BALF) during pneumonia with strains PA103 and PA103-29. Lung levels of cytokines (tumor necrosis factor-alpha, interleukin-6) and chemokines (macrophage inflammatory protein-2, KC) were higher in mice inoculated with strain PA103, whereas BALF concentrations of NO were similar in mice treated with strains PA103 and PA103-29. These data suggest that P-ExA impairs host defence during pneumonia caused by P. aeruginosa by a mechanism that does not involve effects on neutrophil influx, cytokines, chemokines or NO formation.