Characterization of host responses during Pseudomonas aeruginosa acute lung infection in the lungs and blood and after treatment with the synthetic immunomodulatory peptide IDR-1002
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ABSTRACT:
PROVIDER: PRJNA433662 | ENA |
REPOSITORIES: ENA
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Project description:Pseudomonas aeruginosa is an opportunistic pathogen that causes nosocomial pneumonia and infects patients with cystic fibrosis. P. aeruginosa lung infections are difficult to treat due to bacterial resistance to antibiotics, and strains with multi-drug resistance are becoming more prevalent. Here we examined the use of a small host defense peptide, innate defense regulator 1002 (IDR-1002), in an acute P. aeruginosa lung infection in vivo. IDR-1002 significantly reduced the bacterial burden in the bronchoalveolar lavage fluid (BALF) as well as MCP-1 in the BALF and serum, KC in the serum, and IL-6 in the BALF. RNA-Seq was conducted on lungs and whole blood and the effects of P. aeruginosa, IDR-1002, or the combination of P. aeruginosa and IDR-1002 were evaluated. Differential gene expression analysis showed that P. aeruginosa increased multiple inflammatory and innate immune pathways as well as affected hemostasis, matrix metalloproteinases, collagen biosynthesis, and various metabolism pathways in the lungs and/or blood. Infected mice treated with IDR-1002 had significant changes in gene expression compared to untreated infected mice, with fewer differentially expressed genes associated with the inflammatory and innate immune responses to microbial infection, and treatment also affected morphogenesis, certain metabolic pathways, and lymphocyte activation. Overall, these results show that IDR-1002 was effective in treating P. aeruginosa acute lung infections and associated inflammation.
2018-10-29 | GSE110415 | GEO
Project description:Innate defense regulator (IDR) peptide-1002 is a synthetic host defense peptide derivative with strong anti-inflammatory properties.To investigate the anti-inflammatory mechanisms of IDR-1002 in vivo, the phorbol 12-myristate 13-acetate (PMA)-induced mouse ear inflammation model was used. Topical IDR-1002 treatment successfully dampened PMA-induced ear edema, proinflammatory cytokine production, reactive oxygen and nitrogen species release, and neutrophil recruitment in the ears of CD1 mice. Advanced RNA-Seq analysis on the mouse ear transcriptome revealed that IDR-1002 reduced sterile inflammation by suppressing the expression of transmembrane G-protein coupled receptors (Class A/1 rhodopsin-like), including receptors for chemokines, prostaglandins, histamine, platelet activating factor and anaphylatoxin. IDR-1002 also dampened IFNγ response and repressed the Interferon regulatory factor (Irf) 8-regulated network that controls central inflammatory pathways.
2018-01-31 | GSE100918 | GEO
Project description:Perinatal brain injury is a major clinical problem associated with high neonatal mortality and morbidity and an increased risk of life-long chronic disabilities. Despite improved survival rates, the absolute numbers of neurological handicaps of perinatal origin have not decreased. There is currently no pharmacological treatment providing neuroprotction in neonates. As activation of the innate immune response is a key contributing factor to brain injury in both term and preterm infants we investigated the therapeutic potential of novel immunomodulatory innate defence regulator peptides (IDRs) in perinatal brain injury. IDR-1018 significantly reduced the production of inflammatory mediators by LPS-stimulated microglia cells in vitro. IDR-1018 was also neuroprotective in a clinically-relevant animal model of neonatal brain injury, exerting effects on regulatory molecules of TLR-, Ca2+- and p53-signaling. Of utmost importance, IDR-1018 markedly protected both white and grey brain matter when administered after the injury, thus has tremendous applicability to the clinical setting. Here we demonstrate for the first time that peripheral administration of an immunomodulatory peptide is neuroprotective in vivo in a clinically relevant model of perinatal brain damage.
2016-09-17 | GSE36215 | GEO
Project description:Perinatal brain injury is a major clinical problem associated with high neonatal mortality and morbidity and an increased risk of life-long chronic disabilities. Despite improved survival rates, the absolute numbers of neurological handicaps of perinatal origin have not decreased. There is currently no pharmacological treatment providing neuroprotction in neonates. As activation of the innate immune response is a key contributing factor to brain injury in both term and preterm infants we investigated the therapeutic potential of novel immunomodulatory innate defence regulator peptides (IDRs) in perinatal brain injury. IDR-1018 significantly reduced the production of inflammatory mediators by LPS-stimulated microglia cells in vitro. IDR-1018 was also neuroprotective in a clinically-relevant animal model of neonatal brain injury, exerting effects on regulatory molecules of TLR-, Ca2+- and p53-signaling. Of utmost importance, IDR-1018 markedly protected both white and grey brain matter when administered after the injury, thus has tremendous applicability to the clinical setting. Here we demonstrate for the first time that peripheral administration of an immunomodulatory peptide is neuroprotective in vivo in a clinically relevant model of perinatal brain damage. In this second data set, adult mice were used for comparison.
2016-09-17 | GSE51026 | GEO
Project description:Synthetic, innate defense regulators (IDR) peptides, designed based on natural host defenses peptides, have enhanced immunomodulatory activities and reduced toxicity leading to protection in infection and inflammation models that is dependent on macrophages/monocytes. Here we measured the effect of IDR-1018 on macrophage gene expression during differentiation. Differentiation in the presence of IDR-1018 induced a unique signature of immune responses suggesting that IDR-1018 drives macrophage differentiation towards an intermediate M1-M2 state, enhancing anti-inflammatory functions while maintaining certain pro-inflammatory activities important to the resolution of infection. RNA-seq was performed using the Illumina Genome Analyzer IIx platform. Monocytes were isolated from 3 healthy donors, and left unstimulated or stimulated for 4 hours with 20 μg/ml IDR-1018. For library preparation, 500 ng of total RNA was processed according to the Illumina TruSeq RNA sample preparation guide (Illumina catalogue number FC-122-1002). Briefly, mRNA was purified using poly-dT beads, followed by synthesis of the first and second cDNA strands, end repair addition of an poly-A overhang, and ligation of adapters and unique barcodes, as per the manufacturer’s instructions. DNA enrichment was carried out via a 15-cycle PCR. Following quantification, 8 pM of dsDNA was used for cluster generation on a CBOT instrument (Illumina, San Diego, CA). RNA sequencing was done on a GAIIx instrument (Illumina), performed as a single read run with 51 amplification cycles. Data processing was carried out in house, using CASAVA to convert raw data and demultiplex to FASTQ sequence files. Reads were aligned to the reference genome using TOPHAT, and then mapped to genes using the Bioconductor package GenomeRanges.
2013-10-16 | E-GEOD-40131 | biostudies-arrayexpress
Project description:Genome-wide gene expression was measured in peripheral blood mononuclear cells (PBMCs) from patients with cystic fibrosis (CF) after treatment in vitro with the flagellin protein fliC, and/or synthetic peptide IDR-1018 to assess patterns of gene expression. The patterns of gene expression suggest that CF cells have a hyperinflammatory phenotype including dysfunctional autophagy processes. The synthetic peptide IDR-1018 attentuates this hyperinflammatory phenotype. Total RNA was obtained from PBMCs obtained from CF patients after treatment with the fliC flagellin protein (that is known to play a role in CF lung inflammation), and/or the peptide IDR-1018 that has anti-inflammatory properties. Comparison of genes and pathways affected by these treatments indicated the role of autophagy process in CF disease.
2012-11-20 | E-GEOD-35394 | biostudies-arrayexpress
Project description:Genome-wide gene expression was measured in peripheral blood mononuclear cells (PBMCs) from patients with cystic fibrosis (CF) after treatment in vitro with the flagellin protein fliC, and/or synthetic peptide IDR-1018 to assess patterns of gene expression. The patterns of gene expression suggest that CF cells have a hyperinflammatory phenotype including dysfunctional autophagy processes. The synthetic peptide IDR-1018 attentuates this hyperinflammatory phenotype.
2012-11-20 | GSE35394 | GEO
Project description:Synthetic, innate defense regulators (IDR) peptides, designed based on natural host defenses peptides, have enhanced immunomodulatory activities and reduced toxicity leading to protection in infection and inflammation models that is dependent on macrophages/monocytes. Here we measured the effect of IDR-1018 on macrophage gene expression during differentiation. Differentiation in the presence of IDR-1018 induced a unique signature of immune responses suggesting that IDR-1018 drives macrophage differentiation towards an intermediate M1-M2 state, enhancing anti-inflammatory functions while maintaining certain pro-inflammatory activities important to the resolution of infection.
2013-10-16 | GSE40131 | GEO
Project description:Genome-wide gene expression was measured in two cell lines: CF bronchial epithelial cell line IB3-1 (compound heterozygote for the ΔF508 and W1282X CFTR mutations) and the isogenic, CFTR-corrected C38 cell line, after treatment with the flagellin protein FliC, and/or synthetic peptide IDR-1018. Total RNA was obtained from cell lines representing CF and normal epithelial cells after treatment with the fliC protein (that is known to play a role in CF lung inflammation), and/or the peptide IDR-1018 that has anti-inflammatory properties. Comparison of genes and pathways affected by these treatments indicated the role of autophagy process in CF disease.
2012-11-05 | E-GEOD-35391 | biostudies-arrayexpress
Project description:Effect of peptide IDR-1 on CD14+ human monocytes. >br< >br< Effect of peptide IDR-1 on LPS-induced responses in CD14+ human monocytes.>br< >br< Human peripheral blood mononuclear cells (PBMC) were treated with innate defence regulator peptide IDR-1 in the presence and absence of LPS (purified from Pseudomonas aeruginosa) for 4hrs. The objective was to obtain a transcriptional profile of responses induced by IDR-1 and the effect of IDR-1 on LPS-induced transcription.
2007-04-10 | E-FPMI-8 | biostudies-arrayexpress