Bactericidal/Permeability-Increasing Protein Is an Enhancer of Bacterial Lipoprotein Recognition.

André Gessner,Martina Toelge,Franziska Waldow,Sven Hammerschmidt,Maren Werner,Sigrid Bülow,Thomas Schubert,Clemens Entzian,Nicolas Gisch,Jonas Holzinger,Lisa Zeller

doi:10.3389/fimmu.2018.02768

Abstract

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, bactericidal/permeability-increasing protein (BPI) neutralizes endotoxic activity of lipopolysaccharides, and thus prohibits hyperactivation. So far, no immunological function of BPI has been described in Gram-positive infections. Here, we show a significant elevation of BPI in Gram-positive meningitis and, surprisingly, a positive correlation between BPI and pro-inflammatory markers like TNFα. To clarify the underlying mechanisms, we identify BPI ligands of Gram-positive origin, specifically bacterial lipopeptides and lipoteichoic acids, and determine essential structural motifs for this interaction. Importantly, 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. In conclusion, we define BPI as an immune enhancing pattern recognition molecule in Gram-positive infections.

Highlights

Pathogen-associated molecular patterns (PAMPs) of bacterial origin like lipopolysaccharide (LPS) are recognized by innate immune cells via a variety of pattern recognition receptors
In the case of Gram-positive meningitis, we focused on S. pneumoniae (n = 13), and in Gram-negative meningitis on N. meningitidis (n = 7)
In cerebrospinal fluid (CSF) of patients with meningitis caused by N. meningitidis, no tendency was observed for a positive correlation between Bactericidal/permeability-increasing protein (BPI) and either TNFα or IL6 levels (Figure S2)

Summary

Introduction

Pathogen-associated molecular patterns (PAMPs) of bacterial origin like lipopolysaccharide (LPS) are recognized by innate immune cells via a variety of pattern recognition receptors. In Gram-positive infections, the most important PAMPs are bacterial lipopeptides and lipoproteins [bLPs; [2, 3]]. Their extracellular recognition is mediated by TLR2 [2, 3]. In this process, formation of a heterodimer between TLR2 and TLR6 or TLR1 is essential for the perception of di-acylated or tri-acylated bLPs, respectively [4, 5]. Lipopolysaccharide binding protein (LBP) contributes to the recognition of both LPS and bLPs

Methods

Results

Conclusion