Protection against FatalPseudomonas aeruginosaPneumonia in Mice after Nasal Immunization with a Live, AttenuatedaroADeletion Mutant

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Abstract
Studies of immunity toPseudomonas aeruginosahave indicated that a variety of potential immunogens can elicit protection in animal models, utilizing both antibody- and cell-mediated immune effectors for protection. To attempt to optimize delivery of multiple protective antigens and elicit a broad range of immune effectors, we produced anaroAdeletion mutant of theP. aeruginosaserogroup O2/O5 strain PAO1, designated PAO1ΔaroA. Previously, we reported that this strain elicits high levels of opsonic antibody directed against many serogroup O2/O5 strains after nasal immunization of mice and rabbits. Here, we assessed the protective efficacy of immunization with PAO1ΔaroAagainst acute fatal pneumonia in mice. After active immunization, high levels of protection were achieved against an ExoU-expressing cytotoxic variant of the parental strain PAO1 at doses up to 1,000-fold greater than the 50% lethal dose. Significant protection against PAO1 and two of four other serogroup O2/O5 strains was also found, but there was no protection against serogroup-heterologous strains. The serogroup O2/O5 strains not protected against were killed in opsonophagocytic assays as efficiently as the strains with which protection was seen, indicating a lack of correlation of protection and opsonic killing within the serogroup. In passive immunization experiments using challenge with wild-type PAO1 or other noncytotoxic members of the O2/O5 serogroup, there was no protection despite the presence of high levels of opsonic antibody in the mouse sera. However, passive immunization did prevent mortality from pneumonia due to the cytotoxic PAO1 variant at low-challenge doses. These data suggest that a combination of humoral and cellular immunity is required for protection againstP. aeruginosalung infections, that such immunity can be elicited by usingaroAdeletion mutants, and that a multivalentP. aeruginosavaccine composed ofaroAdeletion mutants of multiple serogroups holds significant promise.