Mechanism of immune escape by mycobacteria via TREM2 in mice.

TREM2 inhibits the Mincle-FcRγ-CARD9 pathway and reduces iNOS to kill bacteria. On the other hand, TREM2 promotes the synthesis and release of monocyte chemotactic protein (MCP)-1 to recruit permissive macrophages to enhance infectivity [42]. The illustration rendering portion of this work was supported by Figdraw (https://www.figdraw.com/). TREM2, triggering receptor expressed on myeloid cells 2; CARD9, caspase-recruitment domain family member 9; SYK, splenic tyrosine kinase; DAP12, DNAX activation protein 12; BCL10, B cell lymphoma 10; iNOS, inducible nitric oxide synthase; MALT1, mucosa-associated lymphoid tissue translocation protein 1.</p

The antimicrobial effects of TREM2 on barrier immune cells.

(A) TREM2 expression in acne lesions enhances the phagocytic capacity of macrophages against lipids and bacteria, but the macrophages do not facilitate microbial bacterial clearance due to the ability of squalene to clear ROS and to inhibit ROS production [25]. (B) TREM2 inhibits C1q transcription and basal C1q production by suppressing PPAR-δ activity in AMs, and C1q was up-regulated in Trem2-/- AMs to enhance macrophage phagocytosis [45]. The illustration rendering portion of this work was supported by Figdraw (https://www.figdraw.com/). TREM2, triggering receptor expressed on myeloid cells 2; ROS, reactive oxygen species; C1q, complement 1q; PPAR-δ, peroxisome proliferator-activated receptor-δ; AMs, alveolar macrophages; DAP12, DNAX activation protein 12.</p

The role of TREM2 in regulating bacterial phagocytosis, clearance and the release of inflammatory factors^α.

The role of TREM2 in regulating bacterial phagocytosis, clearance and the release of inflammatory factorsα.</p

The role of TREM2 in bacterial infection.

(A) TREM2 binds to lipid components on bacteria via the hydrophobic and cationic regions of extracellular fragments and progressively activates SYK, PI3K, and GTPases via the ITAM motif of DAP12. GTPases rearrange of actin-rich formation near the bacteria, allowing the bacteria to be internalized by the surrounding membrane [41,53]. (B) TREM2 inhibits NLRP3 inflammasome transcription and assembly by stabilizing β-catenin and reducing mitochondrial ROS release, which in turn inhibits cell pyroptosis and IL-1β release. In addition, AKT and PKC downstream of TREM2 can stimulate NADPH oxidase complex on phagosomes to release ROS, promoting bacterial killing [46,48,50]. The illustration rendering portion of this work was supported by Figdraw (https://www.figdraw.com/). TREM2, triggering receptor expressed on myeloid cells 2; SYK, splenic tyrosine kinase; PI3K, phosphoinositide 3-kinase; ITAM, immunoreceptor tyrosine activator motif; DAP12, DNAX activation protein 12; NLRP3, NACHT, LRR, and PYD domains-containing protein 3; ROS, reactive oxygen species; IL, interleukin; NADPH, nicotinamide adenine dinucleotide phosphate; GSMDM, gesdermin D; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; DAG, diacylglycerol; AKT, protein kinase B; PKC, protein kinase C.</p

Additional file 1: of The role of increased body mass index in outcomes of sepsis: a systematic review and meta-analysis

The role of increased body mass index in outcomes of sepsis: A systematic review and meta-analysis. (DOCX 385 kb

Self-Assembling Myristoylated Human α‑Defensin 5 as a Next-Generation Nanobiotics Potentiates Therapeutic Efficacy in Bacterial Infection

The increasing prevalence of antibacterial resistance globally underscores the urgent need to the update of antibiotics. Here, we describe a strategy for inducing the self-assembly of a host-defense antimicrobial peptide (AMP) into nanoparticle antibiotics (termed nanobiotics) with significantly improved pharmacological properties. Our strategy involves the myristoylation of human α-defensin 5 (HD5) as a therapeutic target and subsequent self-assembly in aqueous media in the absence of exogenous excipients. Compared with its parent HD5, the C-terminally myristoylated HD5 (HD5-myr)-assembled nanobiotic exhibited significantly enhanced broad-spectrum bactericidal activity <i>in vitro</i>. Mechanistically, it selectively killed Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) through disruption of the cell wall and/or membrane structure. The <i>in vivo</i> results further demonstrated that the HD5-myr nanobiotic protected against skin infection by MRSA and rescued mice from E. coli-induced sepsis by lowering the systemic bacterial burden and alleviating organ damage. The self-assembled HD5-myr nanobiotic also showed negligible hemolytic activity and substantially low toxicity in animals. Our findings validate this design rationale as a simple yet versatile strategy for generating AMP-derived nanobiotics with excellent <i>in vivo</i> tolerability. This advancement will likely have a broad impact on antibiotic discovery and development efforts aimed at combating antibacterial resistance

Self-Assembling Myristoylated Human α‑Defensin 5 as a Next-Generation Nanobiotics Potentiates Therapeutic Efficacy in Bacterial Infection

The increasing prevalence of antibacterial resistance globally underscores the urgent need to the update of antibiotics. Here, we describe a strategy for inducing the self-assembly of a host-defense antimicrobial peptide (AMP) into nanoparticle antibiotics (termed nanobiotics) with significantly improved pharmacological properties. Our strategy involves the myristoylation of human α-defensin 5 (HD5) as a therapeutic target and subsequent self-assembly in aqueous media in the absence of exogenous excipients. Compared with its parent HD5, the C-terminally myristoylated HD5 (HD5-myr)-assembled nanobiotic exhibited significantly enhanced broad-spectrum bactericidal activity <i>in vitro</i>. Mechanistically, it selectively killed Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) through disruption of the cell wall and/or membrane structure. The <i>in vivo</i> results further demonstrated that the HD5-myr nanobiotic protected against skin infection by MRSA and rescued mice from E. coli-induced sepsis by lowering the systemic bacterial burden and alleviating organ damage. The self-assembled HD5-myr nanobiotic also showed negligible hemolytic activity and substantially low toxicity in animals. Our findings validate this design rationale as a simple yet versatile strategy for generating AMP-derived nanobiotics with excellent <i>in vivo</i> tolerability. This advancement will likely have a broad impact on antibiotic discovery and development efforts aimed at combating antibacterial resistance

Self-Assembling Myristoylated Human α‑Defensin 5 as a Next-Generation Nanobiotics Potentiates Therapeutic Efficacy in Bacterial Infection

The increasing prevalence of antibacterial resistance globally underscores the urgent need to the update of antibiotics. Here, we describe a strategy for inducing the self-assembly of a host-defense antimicrobial peptide (AMP) into nanoparticle antibiotics (termed nanobiotics) with significantly improved pharmacological properties. Our strategy involves the myristoylation of human α-defensin 5 (HD5) as a therapeutic target and subsequent self-assembly in aqueous media in the absence of exogenous excipients. Compared with its parent HD5, the C-terminally myristoylated HD5 (HD5-myr)-assembled nanobiotic exhibited significantly enhanced broad-spectrum bactericidal activity <i>in vitro</i>. Mechanistically, it selectively killed Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) through disruption of the cell wall and/or membrane structure. The <i>in vivo</i> results further demonstrated that the HD5-myr nanobiotic protected against skin infection by MRSA and rescued mice from E. coli-induced sepsis by lowering the systemic bacterial burden and alleviating organ damage. The self-assembled HD5-myr nanobiotic also showed negligible hemolytic activity and substantially low toxicity in animals. Our findings validate this design rationale as a simple yet versatile strategy for generating AMP-derived nanobiotics with excellent <i>in vivo</i> tolerability. This advancement will likely have a broad impact on antibiotic discovery and development efforts aimed at combating antibacterial resistance