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Infection and Immunity, January 2007, p. 342-349, Vol. 75, No. 1
0019-9567/07/$08.00+0     doi:10.1128/IAI.01089-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Amit Srivastava, Heather Casey, Nathaniel Johnson, Ofer Levy, and Richard Malley*

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.

* Corresponding author. Mailing address: Division of Infectious Diseases, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. Phone: (617) 919-2902. Fax: (617) 730-0255. E-mail: richard.malley{at}childrens.harvard.edu.

{triangledown} Published ahead of print on 13 November 2006.

Editor: J. N. Weiser

Infection and Immunity, January 2007, p. 342-349, Vol. 75, No. 1
0019-9567/07/$08.00+0     doi:10.1128/IAI.01089-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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