AN OPSONIC FUNCTION OF THE NEUTROPHIL BACTERICIDAL PERMEABILITY-INCREASING PROTEIN DEPENDS ON BOTH ITS N-TERMINAL AND C-TERMINAL DOMAINS

The host response to Gram-negative bacterial infection is influenced b y two homologous lipopolysaccharide (LPS)-interactive proteins, LPS-bi nding protein (LBP) and the bacteridical/permeability-increasing prote in (BPI), Both proteins bind LPS via their N-terminal domains but prod uce profoundly different effects: BPI and a bioactive N-terminal fragm ent BPI-21 exert a selective and potent antibacterial effect upon Gram -negative bacteria and suppress LPS bioactivity whereas LBP is not tox ic toward Gramnegative bacteria and potentiates LPS bioactivity, The l atter effect of LBP requires the C-terminal domain for delivery of LPS to CD14, so we postulated that the C-terminal region of BPI may serve a similar delivery function but to distinct targets, LBP, holoBPI, BP I-21, and LBP/BPI chimeras were compared for their ability to promote uptake by human phagocytes of an encapsulated, phagocytosis-resistant strain of Escherichia coli, We show that only bacteria preincubated wi th holoBPI are ingested by neutrophils and monocytes, These findings s uggest that, when extracellular holoBPI is bound via its N-terminal do main to Gram-negative bacteria, the C-terminal domain promotes bacteri al attachment to neutrophils and monocytes, leading to phagocytosis. T herefore, analogous to the role of the C-terminal domain of LBP in del ivery of LPS to CD14, the C-terminal domain of BPI may fulfill a simil ar function in BPI-specific disposal pathways for Gram-negative bacter ia.