Scavenging of bacteria or bacterial products by magnetic particles functionalized with a broad-spectrum pathogen recognition receptor motif offers diagnostic and therapeutic applications

• Published in: Acta biomaterialia 2022-03, Vol.141, p.418-428
• Main Authors: Friedrich, Bernhard, Lyer, Stefan, Janko, Christina, Unterweger, Harald, Brox, Regine, Cunningham, Sarah, Dutz, Silvio, Taccardi, Nicola, Bikker, Floris J., Hurle, Katrin, Sebald, Heidi, Lenz, Malte, Spiecker, Erdmann, Fester, Lars, Hackstein, Holger, Strauß, Richard, Boccaccini, Aldo R., Bogdan, Christian, Alexiou, Christoph, Tietze, Rainer
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; Antibiotics; Bacteria; Bacteria - metabolism; Biomimetics; Cytokines; Cytokines - metabolism; Depletion; E coli; Endotoxins; Escherichia coli - metabolism; GP-340; Humans; IL-1β; Immune response; Infections; Interleukin 10; Interleukin 6; Iron oxides; Magnetic nanoparticles; Magnetic Phenomena; Nanoparticles; Pathogen binding; Pathogens; Pattern recognition; Peptides; Peptides - therapeutic use; Pseudomonas aeruginosa; Receptors; Scavenger receptors; Scavenging; Sepsis; Sepsis - drug therapy; SRCR domain; Staphylococcus aureus - metabolism; Therapeutic applications; Tumor necrosis factor; γ-Interferon
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2022.01.001

Sepsis is a dysregulated host response of severe bloodstream infections, and given its frequency of occurrence and high mortality rate, therapeutic improvements are imperative. A reliable biomimetic strategy for the targeting and separation of bacterial pathogens in bloodstream infections involves the use of the broad-spectrum binding motif of human GP-340, a pattern-recognition receptor of the scavenger receptor cysteine rich (SRCR) superfamily that is expressed on epithelial surfaces but not found in blood. Here we show that these peptides, when conjugated to superparamagnetic iron oxide nanoparticles (SPIONs), can separate various bacterial endotoxins and intact microbes (E. coli, S. aureus, P. aeruginosa and S. marcescens) with high efficiency, especially at low and thus clinically relevant concentrations. This is accompanied by a subsequent strong depletion in cytokine release (TNF, IL-6, IL-1β, Il-10 and IFN-γ), which could have a direct therapeutic impact since escalating immune responses complicates severe bloodstream infections and sepsis courses. SPIONs are coated with aminoalkylsilane and capture peptides are orthogonally ligated to this surface. The particles behave fully cyto- and hemocompatible and do not interfere with host structures. Thus, this approach additionally aims to dramatically reduce diagnostic times for patients with suspected bloodstream infections and accelerate targeted antibiotic therapy. Sepsis is often associated with excessive release of cytokines. This aspect and slow diagnostic procedures are the major therapeutic obstacles. The use of magnetic particles conjugated with small peptides derived from the binding motif of a broad-spectrum mucosal pathogen recognition protein GP-340 provides a highly efficient scavenging platform. These peptides are not found in blood and therefore are not subject to inhibitory mechanisms like in other concepts (mannose binding lectine, aptamers, antibodies). In this work, data are shown on the broad bacterial binding spectrum, highly efficient toxin depletion, which directly reduces the release of cytokines. Host cells are not affected and antibiotics not adsorbed. The particle bound microbes can be recultured without restriction and thus be used directly for diagnostics. [Display omitted]