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The transition to antibiotic-free poultry production in the face of pathogenic threats is a very challenging task. We recently demonstrated that mucosal delivery of CpG-ODN alone by the intrapulmonary route (IPL) has potential as an effective alternative to antibiotics in neonatal chicks against Escherichia coli septicemia. How exactly mucosal delivery of CpG-ODN elicits, protective antibacterial immunity remained poorly understood. In this study, CpG-ODN or saline was delivered via the intrapulmonary route to day-old chicks (n = 80/group) using a compressor nebulizer in an acrylic chamber (1 mg/mL CpG-ODN for 15 minutes). In the first part of the study, two days after mucosal CpG-ODN delivery, 40 chicks from each group were challenged subcutaneously with 1 × 10 cfu (n = 20) or 1 × 10 cfu (n = 20) of E. coli and the mortality pattern was monitored for seven days. We found significantly higher survival, better clinical conditions and lower bacterial loads in chicks that received mucosal CpG-ODN. To explore the mechanisms behind this protective immunity, we first looked at the kinetics of the cytokine gene expression (three birds/ group/ time for 10 time-points) in the lungs and spleens. Multiplex gene analysis demonstrated a significant elevation of pro-inflammatory cytokine genes mRNA in the CpG-ODN group. Interleukin (IL)-1β robustly upregulated many folds in the lung after CpG-ODN delivery. Lipopolysaccharide-induced tumor necrosis factor (LITAF) and IL-18 showed expression for an extended period in the lungs. Anti-inflammatory cytokine IL-10 was upregulated in both lungs and spleen, whereas IL-4 showed upregulation in the lungs. To investigate the kinetics of immune enrichment in the lungs and spleens, we performed flow cytometry, histology, and immunohistochemistry at 24, 48 and 72 hrs after CpG-ODN delivery. CpG-ODN treated lungs showed a significant enrichment with monocytes/macrophages and CD4 and CD8 T-cell subsets. Macrophages in CpG-ODN treated group demonstrated mature phenotypes (higher CD40 and MHCII expression). Importantly, mucosal delivery of CpG-ODN via the intrapulmonary route significantly enriched immune compartment in the spleen as well, suggesting a systemic effect in neonatal chicks. Altogether, intrapulmonary delivery of aerosolized CpG-ODN orchestrates protective immunity against E. coli septicemia by not only enhancing mucosal immunity but also the systemic immune responses.
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http://dx.doi.org/10.1038/s41598-020-61683-y | DOI Listing |
Small
December 2024
Chair of Macromolecular Chemistry, Institute of Functional Materials and Biofabrication, Faculty of Chemistry and Pharmacy, Julius -Maximilians-Universität-Würzburg, Röntgenring 11, 97070, Würzburg, Germany.
Cationic, core-crosslinked nanogel particles are prepared from synthetic biodegradable materials. These fully hydrophilic nanogels offer superior customizability compared to common lipid nanoparticles, thereby circumventing intrinsic immune stimulatory properties. Electrostatic loading allows for complexation of nucleic acids including the immune stimulatory Toll-like receptor 9 (TLR9) agonistCpG-ODN (cytidine-phosphate-guanosine oligodeoxynucleotide).
View Article and Find Full Text PDFPharmaceutics
October 2024
Department of Applied Chemistry, Faculty of Engineering, Aichi Institute of Technology, 1247 Yachigusa, Yakusa-cho, Toyota 470-0392, Japan.
Nucleic acid medicines are a highly attractive modality that act in a sequence-specific manner on target molecules. To date, 21 such products have been approved by the Food and Drug Administration. However, the development of nucleic acid medicines continues to face various challenges, including tissue and cell targeting as well as intracellular delivery.
View Article and Find Full Text PDFSci Rep
November 2024
Concept Life Sciences, Edinburgh, Scotland.
Mol Pharm
December 2024
Kinimmune Inc., Saint Louis, Missouri 63141, United States.
Unmethylated cytosine-guanine oligodeoxynucleotides (CpG ODNs) have a storied history as agonists for Toll-like receptor 9 (TLR9). CpG ODNs have shown promising antitumor effects in preclinical studies by inducing potent proinflammatory immune responses. However, clinical success has been hindered by inconsistent efficacy and immune-related toxicities caused by systemic exposure to CpG ODNs.
View Article and Find Full Text PDFAdv Healthc Mater
October 2024
Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, NM, 87131, USA.
Intraperitoneal (IP) administration of immunogenic mesoporous silica nanoparticles (iMSN) in a mouse model of metastatic ovarian cancer promotes the development of tumor-specific CD8 T cells and protective immunity. IP delivery of iMSN functionalized with the Toll-like receptor (TLR) agonists polyethyleneimine (PEI), CpG oligonucleotide, and monophosphoryl lipid A (MPLA) stimulated rapid uptake by all peritoneal myeloid subsets. Myeloid cells quickly transported iMSN to milky spots and fat-associated lymphoid clusters (FALCs) present in tumor-burdened adipose tissues, leading to a reduction in suppressive T cells and an increase in activated memory T cells.
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