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Bioresponsive Nanoparticles Targeted to Infectious Microenvironments for Sepsis Management.

ABSTRACT: Sepsis is a life-threatening disease resulted from a dysregulated host immune response to bacterial infections, continuing to cause high morbidity and mortality worldwide. Despite discoveries of many potential therapeutic targets, effective treatments of sepsis are lacking. Here, a strategy is reported to target infectious microenvironments (IMEs) via bioresponsive nanoparticles that simultaneously eliminate bacteria and alleviate the host inflammation response, thus managing sepsis in mice. The nanoparticle is made of copolymers sensitive to pH and bacterial enzymes to self-assemble into a micelle loaded with both an antibiotic (ciprofloxacin) and an anti-inflammatory agent ((2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide). In addition, the nanoparticle is conjugated with intercellular adhesion molecule-1 antibodies to target IMEs. Nanoparticle targeting to IMEs and local cues as triggers to deliver therapeutics in on-demand manners is demonstrated using an acute lung bacterial infection mouse model. In the sepsis mouse model induced by peritonitis at a lethal dose of bacterial invasion, it is shown that concurrently targeting pathogens and excessive inflammation pathways is valuable to manage the sepsis. The study illustrates not only the development of a new delivery system but also the mechanism-based therapy of nanomedicine for infectious diseases.

SUBMITTER: Zhang CY

PROVIDER: S-EPMC6197919 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Project description:BackgroundPersistent loss of skeletal muscle mass and function as well as altered fat metabolism are frequently observed in severe sepsis survivors. Studies examining sepsis-associated tissue dysfunction from the perspective of the tissue microenvironment are scarce. In this study, we comprehensively assessed transcriptional changes in muscle and fat at single-cell resolution following experimental sepsis induction.MethodsSkeletal muscle and visceral white adipose tissue from control mice or mice 1 day or 1 month following faecal slurry-induced sepsis were used. Single cells were mechanically and enzymatically prepared from whole tissue, and viable cells were further isolated by fluorescence activated cell sorting. Droplet-based single-cell RNA-sequencing (scRNA-seq; 10× Genomics) was used to generate single-cell gene expression profiles of thousands of muscle and fat-resident cells. Bioinformatics analyses were performed to identify and compare individual cell populations in both tissues.ResultsIn skeletal muscle, scRNA-seq analysis classified 1438 single cells into myocytes, endothelial cells, fibroblasts, mesenchymal stem cells, macrophages, neutrophils, T-cells, B-cells, and dendritic cells. In adipose tissue, scRNA-seq analysis classified 2281 single cells into adipose stem cells, preadipocytes, endothelial cells, fibroblasts, macrophages, dendritic cells, B-cells, T-cells, NK cells, and gamma delta T-cells. One day post-sepsis, the proportion of most non-immune cell populations was decreased, while immune cell populations, particularly neutrophils and macrophages, were highly enriched. Proportional changes of endothelial cells, neutrophils, and macrophages were validated using faecal slurry and cecal ligation and puncture models. At 1 month post-sepsis, we observed persistent enrichment/depletion of cell populations and further uncovered a cell-type and tissue-specific ability to return to a baseline transcriptomic state. Differential gene expression analyses revealed key genes and pathways altered in post-sepsis muscle and fat and highlighted the engagement of infection/inflammation and tissue damage signalling. Finally, regulator analysis identified gonadotropin-releasing hormone and Bay 11-7082 as targets/compounds that we show can reduce sepsis-associated loss of lean or fat mass.ConclusionsThese data demonstrate persistent post-sepsis muscle and adipose tissue disruption at the single-cell level and highlight opportunities to combat long-term post-sepsis tissue wasting using bioinformatics-guided therapeutic interventions.

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Bioresponsive Nanoparticles Targeted to Infectious Microenvironments for Sepsis Management.

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