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Infection and Immunity, March 2003, p. 1453-1461, Vol. 71, No. 3
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.3.1453-1461.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Protection against Fatal Pseudomonas aeruginosa Pneumonia in Mice after Nasal Immunization with a Live, Attenuated aroA Deletion Mutant

Gregory P. Priebe,1,2,3* Gloria J. Meluleni,1 Fadie T. Coleman,1 Joanna B. Goldberg,4 and Gerald B. Pier1

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School,1 Departments of Anesthesia (Critical Care),2 Medicine (Infectious Diseases), Children's Hospital, Boston, Massachusetts,3 University of Virginia, Health Sciences Center, Charlottesville, Virginia4

Received 13 August 2002/ Returned for modification 24 September 2002/ Accepted 21 November 2002

Studies of immunity to Pseudomonas aeruginosa have 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 an aroA deletion mutant of the P. aeruginosa serogroup O2/O5 strain PAO1, designated PAO1{Delta}aroA. 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 PAO1{Delta}aroA against 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 against P. aeruginosa lung infections, that such immunity can be elicited by using aroA deletion mutants, and that a multivalent P. aeruginosa vaccine composed of aroA deletion mutants of multiple serogroups holds significant promise.

* Corresponding author. Mailing address: Channing Laboratory, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-4248. Fax: (617) 525-2510. E-mail: gpriebe{at}rics.bwh.harvard.edu.

Editor: J. N. Weiser

Infection and Immunity, March 2003, p. 1453-1461, Vol. 71, No. 3
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.3.1453-1461.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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