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The Alternative Activation Pathway and Complement Component C3 Are Critical for a Protective Immune Response against Pseudomonas aeruginosa in a Murine Model of Pneumonia

Research Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas—Houston,¹ Department of Biochemistry and Molecular Biology, University of Texas—Houston Medical School, Houston, Texas 77030²

Received 24 July 2003/ Returned for modification 5 September 2003/ Accepted 21 January 2004

Pseudomonas aeruginosa is a leading cause of hospital-acquired pneumonia, and approximately 80% of patients with cystic fibrosis are infected with this bacterium. To investigate the overall role of complement and the complement activation pathways in the host defense against P. aeruginosa pulmonary infection, we challenged C3-, C4-, and factor B-deficient mice with P. aeruginosa via intranasal inoculation. In these studies, C3^–/– mice had a higher mortality rate than C3^+/+ mice. Factor B^–/– mice, but not C4^–/– mice, infected with P. aeruginosa had a mortality rate similar to that of C3^–/– mice, indicating that in this model the alternative pathway of complement activation is required for the host defense against Pseudomonas infection. C3^–/– mice had 6- to 7-fold more bacteria in the lungs and 48-fold more bacteria in the blood than did C3^+/+ mice at 24 h postinfection. In vitro, phagocytic cells from C3^+/+ or C3^–/– mice exhibited a decreased ability to bind and/or ingest P. aeruginosa in the presence of C3-deficient serum compared to phagocytic cells in the presence of serum with sufficient C3. C3^–/– mice displayed a significant increase in neutrophils in the lungs and had higher levels of interleukin-1ß (IL-1ß), IL-6, IL-10, KC, and MIP-2 in the lungs at 24 h postinfection than did C3^+/+ mice. Collectively, these results indicate that complement activation by the alternative pathway is critical for the survival of mice infected with P. aeruginosa and that the protection provided by complement is at least in part due to C3-mediated opsonization and phagocytosis of P. aeruginosa.

Editor: J. N. Weiser

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