Infect. Immun., Aug 1994, 3564-3567, Vol 62, No. 8
Copyright c 1994, American Society for Microbiology
Recombinant human bactericidal/permeability-increasing protein (rBPI23) is a universal lipopolysaccharide-binding ligand
BJ Appelmelk, YQ An, BG Thijs, DM MacLaren and J de Graaff
Department of Medical Microbiology, Vrije Universiteit, Amsterdam, The Netherlands.
A recombinant 23-kDa protein (rBPI23) derived from human bactericidal/permeability-increasing protein (BPI) possesses potent endotoxin-neutralizing abilities in vitro and in vivo. Binding of rBPI23 to those endotoxins (lipopolysaccharides [LPSs]) encountered clinically would be a prerequisite for efficacy in decreasing mortality among patients suffering from gram-negative sepsis and shock, a disease state in which an etiological role for LPS has been implicated. rBPI23 binds well to lipid A (n = 7), to rough-mutant O-chain-deficient LPS (n = 18, Re to Ra chemotypes), to lipid A-core covalently linked to the O chain, to LPSs from clinically relevant serotypes (n = 100), and to bacterial cells (n = 88) of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, the species most often implicated in clinical gram-negative sepsis and shock. Significant binding of rBPI23 to these antigens took place at rBPI23 concentrations of 1 to 500 ng/ml (median, 16 to 32 ng/ml). Binding did not involve 3-deoxy-D-manno- octulosonate of the inner core. Determining the exact epitope recognized by rBPI23 would require further studies with synthetic lipid A substructures. The demonstrated ability of rBPI23 to universally bind LPS provides a sound basis for further testing of its endotoxin- neutralizing abilities, including clinical trials.
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More recent studies have demonstrated a least four types of lipid proteins that BPI binds to and have not found a lipid protein it does not bind to. The possibility exists, and George more cautiously admits, for BPI not to bind to all gram-negative bacteria. I certainly welcome you, Robert S., to add to the debate by carefully explaining the make-up of each gram-negative bacteria in the type of lipid protein it uses in its cell wall. This may help determine which gram-negative bacteria BPI will most likely have a theraputic effect for. Anxiously awaiting your detailed breakdown of the structure of all gram-negative bacteria.
Tharos |
