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The bactericidal/permeability-increasing protein (BPI), a potent element in host-defense against gram-negative
1Department of Medicine and Microbiology, New York University School of Medicine, New York.
Abstract:
The bactericidal/permeability-increasing protein (BPI), is a ca. 55 kDa cytotoxic cationic protein of polymorphonuclear leukocytes (PMN) that is present principally in the azurophilic granules. BPI is toxic only toward Gram-negative bacteria. This target specificity is attributable to the strong attraction of BPI for the lipopolysaccharides (LPS) in the bacterial envelope. BPI also binds with high affinity (apparent Kd 2-5 nM) to a broad range of LPS species and potently inhibits the biologic activities of LPS in vitro. A proteolytically prepared or recombinant ca 25 kDa N-terminal fragment of BPI carries all the antibacterial activities of holo-BPI and is more potent than the holo-protein against more resistant bacteria with S-form LPS in their envelope. The fragment is as active as holo-BPI as an LPS-neutralizing agent in vitro and more potently inhibits cytokine induction by S-form Escherichia coli in whole blood ex vivo. Recombinant forms of both proteins protect animals against the lethal effects of administered LPS.
Insights
The bactericidal/permeability-increasing protein (BPI) and its N-terminal fragment are potent antibacterial agents targeting Gram-negative bacteria by binding lipopolysaccharides (LPS). Both forms protect against LPS-induced lethal effects in animal models.
Area of Science:
- Immunology
- Microbiology
- Biochemistry
Background:
- The bactericidal/permeability-increasing protein (BPI) is a cytotoxic cationic protein found in polymorphonuclear leukocytes.
- BPI exhibits specific toxicity towards Gram-negative bacteria due to its high affinity for lipopolysaccharides (LPS).
Purpose of the Study:
- To investigate the antibacterial activity and LPS-neutralizing capabilities of BPI and its N-terminal fragment.
- To evaluate the therapeutic potential of BPI and its fragment in combating Gram-negative bacterial infections and LPS toxicity.
Main Methods:
- Characterization of BPI and its N-terminal fragment's binding affinity to various LPS species.
- Assessment of antibacterial potency against Gram-negative bacteria, including resistant strains.
- Evaluation of LPS-neutralizing capacity and inhibition of cytokine induction ex vivo.
- In vivo studies using animal models to assess protection against LPS-induced lethality.
Main Results:
- BPI demonstrates potent binding to LPS, inhibiting its biological activities.
- A 25 kDa N-terminal fragment of BPI retains all antibacterial activities and shows enhanced potency against resistant bacteria.
- The BPI fragment is equally effective as holo-BPI in neutralizing LPS in vitro and more potent in inhibiting cytokine induction.
- Recombinant forms of BPI and its fragment provide protection in animal models against lethal LPS administration.
Conclusions:
- The N-terminal fragment of BPI is a highly potent antibacterial agent with retained LPS-neutralizing properties.
- BPI and its fragment represent promising therapeutic candidates for treating Gram-negative infections and LPS-mediated conditions.