BPI

What is BPI protein?

BPI (bactericidal permeability increasing protein) gene is a protein coding gene which situated on the long arm of chromosome 20 at locus 20q11. It is an endogenous antimicrobial protein that is mainly present in the azulocyte granules of neutrophils. It usually consists of two similar domains, each about 40-50 kDA. The N-terminal domain is responsible for binding to lipopolysaccharide (LPS) in the bacterial outer membrane, while the C-terminal domain is involved in bacterial killing. The BPI protein is consisted of 487 amino acids and its molecular mass is approximately 53.9 kDa.

What is the function of BPI protein?

By interacting with lipopolysaccharide (LPS) of the bacterial outer membrane, the integrity of the bacterial outer membrane is destroyed, thereby specifically binding and killing Gram-negative bacteria; BPI also neutralizes free endotoxins (LPS) and reduces their stimulation of the host immune system, thereby reducing the risk of sepsis and other endotoxin-related diseases. In addition, it is also involved in regulating inflammatory responses, promoting wound healing and other biological processes.

Fig2. Proposed model of BPI functions in bactericidal, anti-inflammatory, and opsonophagocytosis of Pseudomonas aeruginosa. (Jomkuan Theprungsirikul, 2021)

BPI Related Signaling Pathway

The most important is that BPI can neutralize the inflammatory effect of LPS and accelerate the clearance of LPS from circulation, thus affecting the LPS-activated signaling pathway. BPI regulates the immune response by binding to toll-like receptors such as TLR2 and TLR4. By binding to TLR, BPI activates the NF-κB (nuclear factor κB) signaling pathway, which enhances the inflammatory response.

BPI Related Diseases

BPI is a component of the natural immune system, and its deficiency or abnormal function may lead to increased susceptibility to bacterial infections. It is found in neutrophils and protects against respiratory infections and bacterial pneumonia, and abnormal functioning of BPI may increase a patient's risk of developing lung infections. And some inflammatory diseases, immune deficiency diseases, sepsis and so on.

Fig2. Model of BPI functions in the lung during (A) acute pneumonia and (B) CF. (Alexander Holweg, 2011)

Bioapplications of BPI

rhBPI21 is currently an FDA-approved drug for the treatment of acute respiratory distress Syndrome (ARDS). Because BPI can specifically bind to and kill Gram-negative bacteria, it is expected to be an effective anti-infective drug for the treatment of sepsis and other bacterial infections.

Case study 1: Sigrid Bülow, 2018

Adequate perception of immunologically important pathogen-associated molecular patterns like lipopolysaccharide and bacterial lipoproteins is essential for efficient innate and adaptive immune responses. In the context of Gram-negative infection, BPI neutralizes endotoxic activity of lipopolysaccharides, and thus prohibits hyperactivation. So far, no immunological function of BPI has been described in Gram-positive infections.

In this study, a significant elevation of BPI in Gram-positive meningitis and a positive correlation between BPI and pro-inflammatory markers like TNFα were found. To clarify the underlying mechanisms, the team prepared recombinant BPI, bacterial lysates and various methods including BPI microtiter binding assay, nanoDSF experiments and microscale thermophoresis experiments. The results show that the interaction of BPI with these newly defined ligands significantly enhances the immune response in peripheral blood mononuclear cells (PBMCs) mediated by Gram-positive bacteria, and thereby ensures their sensitive perception.

Fig1. Competition of bLPs with lipopolysaccharide for binding to BPI. BPI binding assays with LPS biotin.

Fig2. Influence of BPI on TNFα secretion of PBMCs in response to bLPs and lysates of S. pneumoniae D39Δcps.

Case study 2: Fangchen Gong, 2021

Acute respiratory distress syndrome (ARDS) is one of the leading causes of death in patients with sepsis. As such, early and accurate identification of sepsis-related ARDS is critical. Bioinformatic analysis was used to explore the GEO datasets. ELISA method was used to detect the plasma or cellular supernatant of relevant proteins. Quantitative real-time PCR was used for mRNA measurements and Western blot was applied for protein measurements. Plasma expression of OLFM4 and LCN2 was also upregulated in sepsis-related ARDS patients compared to septic patients alone. In vitro data showed that OLFM4 expression in lung epithelial cells was downregulated upon LPS stimulation, whereas neutrophil media induced OLFM4 expression in lung epithelial cells. Furthermore, the increased levels of LDHA phosphorylation and the downstream NF-κB activation induced by LPS in epithelial cells were effectively diminished by OLFM4 overexpression and recombinant OLFM4 treatment via a reduction in ROS production and HIF1α expression.

Fig3. Analyses of ROC curves of critical DEGs in the GSE66890 dataset.

Fig4. BPI expressions were compared between healthy controls, septic patients, and sepsis-related ARDS patients using ELISA kit.

BPI has several biochemical functions, for example, lipopolysaccharide binding. Some of the functions are cooperated with other proteins, some of the functions could acted by BPI itself. We selected most functions BPI had, and list some proteins which have the same functions with BPI. You can find most of the proteins on our site.

BPI has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with BPI here. Most of them are supplied by our site. Hope this information will be useful for your research of BPI.