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Recombinant Bactericidal/Permeability-Increasing Protein rBPI₂₁ Protects against Pneumococcal Disease

Division of Infectious Diseases, Department of Medicine, Children's Hospital, Boston, Massachusetts

Received 11 July 2006/ Returned for modification 20 September 2006/ Accepted 26 October 2006

Bactericidal/permeability-increasing (BPI) protein has been shown to play an important role in innate immunity to gram-negative bacteria, by direct microbicidal as well as endotoxin-neutralizing action. Here we examined potential interactions between a recombinant 21-kDa bioactive fragment of BPI, rBPI₂₁, and the gram-positive pathogen Streptococcus pneumoniae. rBPI₂₁ bound to pneumococci and pneumolysin (Ply) in a direct and specific fashion. We observed an enhanced inflammatory response in mouse macrophages when rBPI₂₁ was combined with killed pneumococci or supernatant from overnight growth of pneumococci. In addition, rBPI₂₁ augmented the proapoptotic activity of Ply⁺ (but not Ply^–) pneumococci in TLR4-defective murine macrophages (known to be defective also in their apoptotic response to pneumolysin) in a tumor necrosis factor alpha-dependent manner. rBPI₂₁ also enhanced the association of pneumococci with murine macrophages. In a model of invasive pneumococcal disease in TLR4-defective mice, the intranasal administration of rBPI₂₁ following intranasal inoculation of Ply⁺ pneumococci both enhanced upper respiratory tract cell apoptosis and prolonged survival. We have thus discovered a novel interaction between pneumococcus and rBPI₂₁, a potent antimicrobial peptide previously considered to target only gram-negative bacteria.

Published ahead of print on 13 November 2006.

Editor: J. N. Weiser

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