An opsonic function of the neutrophil bactericidal/permeability-increasing protein depends on both its N- and C-terminal domains

Abstract

The host response to Gram-negative bacterial infection is inf luenced by two homologous lipopolysaccharide (LPS)-interactive proteins, LPS-binding protein (LBP) and the bacteridical͞permeability-increasing protein (BPI). Both proteins bind LPS via their N-terminal domains but produce profoundly different effects: BPI and a bioactive N-terminal fragment BPI-21 exert a selective and potent antibacterial effect upon Gram-negative bacteria and suppress LPS bioactivity whereas LBP is not toxic toward Gramnegative bacteria and potentiates LPS bioactivity. The latter 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, BPI-21, and LBP͞BPI 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 with holoBPI are ingested by neutrophils and monocytes. These findings suggest that, when extracellular holoBPI is bound via its N-terminal domain to Gram-negative bacteria, the C-terminal domain promotes bacterial attachment to neutrophils and monocytes, leading to phagocytosis. Therefore, analogous to the role of the C-terminal domain of LBP in delivery of LPS to CD14, the C-terminal domain of BPI may fulfill a similar function in BPI-specific disposal pathways for Gram-negative bacteria.

AML-1, PU.1, and Sp3 regulate expression of human bactericidal/permeability-increasing protein

“…Direct binding of BPI to the bacterial envelope is critical for its antimicrobial action and BPI shows high affinity to the lipid A moiety of lipopolysaccharide (LPS) of Gram-negative bacteria [11]. The structural determinants for the LPS-interaction are located solely in the amino-terminal half of the protein, while an opsonic function of BPI is also dependent on the carboxy-terminal half of the protein [12] (reviewed in [8]). Consistent with its high affinity for LPS, BPI is a paralogue to the acute phase protein lipopolysaccharide-binding protein (LBP) (reviewed in [13]).…”

Evidence of a bactericidal permeability increasing protein in an invertebrate, theCrassostrea gigas Cg-BPI

“…It increases the permeability of the bacterial membranes (10). Accumulated extracellularly, BPI opsonizes bacteria, which enhances phagocytosis by neutrophils (11). LBP and BPI are structurally related, with 45% sequence identity.…”

Identification of BPI protein produced in different expression system and its association with Escherichia coli F18 susceptibility

“…It is primarily present in the aniline blue particles of polymorphonuclear leukocytes, as well as on the surface of mononuclear leucocytes (Iovine et al, 1997;Canny and Levy, 2008). BPI not only kills Gram-negative bacteria (GNB) and neutralizes endotoxins (Akin et al, 2011), but also promotes complement activation and opsonization for increased phagocytosis, inhibits angiogenesis, inhibits the release of inflammatory mediators, and inhibits infection by fungi and protozoa.…”

“…BPI not only kills Gram-negative bacteria (GNB) and neutralizes endotoxins (Akin et al, 2011), but also promotes complement activation and opsonization for increased phagocytosis, inhibits angiogenesis, inhibits the release of inflammatory mediators, and inhibits infection by fungi and protozoa. The function of BPI is related to its structure, which includes a cationic, lysine-rich N-terminus with antibacterial and lipopolysaccharide (endotoxin)-neutralizing activities (Iovine et al, 1997) and a C-terminus that contributes to the stability and opsonic activity (Ooi et al, 1991). BPI also plays an important role in natural defense mechanisms (Weiss et al, 1978;Iovine et al, 1997;Elsbach, 1998).…”

“…The function of BPI is related to its structure, which includes a cationic, lysine-rich N-terminus with antibacterial and lipopolysaccharide (endotoxin)-neutralizing activities (Iovine et al, 1997) and a C-terminus that contributes to the stability and opsonic activity (Ooi et al, 1991). BPI also plays an important role in natural defense mechanisms (Weiss et al, 1978;Iovine et al, 1997;Elsbach, 1998).…”