A Polymorphism of Bactericidal/Permeability-Increasing Protein Affects Its Neutralization Efficiency towards Lipopolysaccharide

• Published in: International journal of molecular sciences 2022-01, Vol.23 (3), p.1324
• Main Authors: Ederer, Katharina U, Holzinger, Jonas M, Maier, Katharina T, Zeller, Lisa, Werner, Maren, Toelge, Martina, Gessner, André, Bülow, Sigrid
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Sequence; Amino acids; Amino Acids - genetics; Amino Acids - metabolism; Animals; Antimicrobial Cationic Peptides - genetics; Antimicrobial Cationic Peptides - metabolism; Bacterial infections; Bactericidal activity; Binding sites; Blood Proteins - genetics; Blood Proteins - metabolism; BPI protein; Cells, Cultured; Cloning; Crystal structure; Cytokines; E coli; Electrostatic properties; Electrostatics; Gene polymorphism; Glutamic acid; Graft versus host disease; Granulocytes; Humans; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Leukocytes (mononuclear); Leukocytes (neutrophilic); Leukocytes, Mononuclear - metabolism; Lipids; Lipopolysaccharides; Lipopolysaccharides - metabolism; Lysine; Mice; Mortality; Neonates; Neutrophils - metabolism; Pediatrics; Peripheral blood mononuclear cells; Permeability; Polymorphism; Polymorphism, Genetic - genetics; Proteins; Sepsis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23031324

Gram-negative sepsis driven by lipopolysaccharide (LPS) has detrimental outcomes, especially in neonates. The neutrophil-derived bactericidal/permeability-increasing protein (BPI) potently neutralizes LPS. Interestingly, polymorphism of the gene at position 645 (rs4358188) corresponds to a favorable survival rate of these patients in the presence of at least one allele 645 A as opposed to 645 G. When we exploited the existing X-ray crystal structure, the corresponding amino acid at position 216 was revealed as surface exposed and proximal to the lipid-binding pocket in the N-terminal domain of BPI. Our further analysis predicted a shift in surface electrostatics by a positively charged lysine (BPI ) exchanging a negatively charged glutamic acid (BPI ). To investigate differences in interaction with LPS, we expressed both BPI variants recombinantly. The amino acid exchange neither affected affinity towards LPS nor altered bactericidal activity. However, when stimulating human peripheral blood mononuclear cells, BPI exhibited a superior LPS-neutralizing capacity (IC 12.0 ± 2.5 pM) as compared to BPI (IC 152.9 ± 113.4 pM, = 0.0081) in respect to IL-6 secretion. In conclusion, we provide a functional correlate to a favorable outcome of sepsis in the presence of BPI .