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The galU Gene of Pseudomonas aeruginosa Is Required for Corneal Infection and Efficient Systemic Spread following Pneumonia but Not for Infection Confined to the Lung

Gregory P. Priebe,^1,2* Charles R. Dean,^3, Tanweer Zaidi,¹ Gloria J. Meluleni,¹ Fadie T. Coleman,¹ Yamara S. Coutinho,¹ Michael J. Noto,³ Teresa A. Urban,³ Gerald B. Pier,¹ and Joanna B. Goldberg³

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital,¹ Departments of Anesthesia (Critical Care) and Medicine (Infectious Diseases), Children's Hospital, Boston, Massachusetts,² Health Sciences Center, University of Virginia, Charlottesville, Virginia³

Received 20 December 2003/ Returned for modification 18 February 2004/ Accepted 10 March 2004

Acute pneumonias and corneal infections due to Pseudomonas aeruginosa are typically caused by lipopolysaccharide (LPS)-smooth strains. In cystic fibrosis patients, however, LPS-rough strains of P. aeruginosa, which lack O antigen, can survive in the lung and cause chronic infection. It is not clear whether an LPS-rough phenotype affects cytotoxicity related to the type III secretion system (TTSS). We previously reported that interruption of the galU gene in P. aeruginosa results in production of a rough LPS and truncated LPS core. Here we evaluated the role of the galU gene in the pathogenesis of murine lung and eye infections and in cytotoxicity due to the TTSS effector ExoU. We studied galU mutants of strain PAO1, of its cytotoxic variant expressing ExoU from a plasmid, and of the inherently cytotoxic strain PA103. The galU mutants were more serum sensitive than the parental strains but remained cytotoxic in vitro. In a corneal infection model, the galU mutants were significantly attenuated. In an acute pneumonia model, the 50% lethal doses of the galU mutants were higher than those of the corresponding wild-type strains, yet these mutants could cause mortality and severe pneumonia, as judged by histology, even with minimal systemic spread. These findings suggest that the galU gene is required for corneal infection and for efficient systemic spread following lung infection but is not required for infection confined to the lung. Host defenses in the lung appear to be insufficient to control infection with LPS-rough P. aeruginosa when local bacterial levels are high.

Editor: J. N. Weiser

Present address: Novartis Institutes for Biomedical Research, Cambridge, Mass.

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