Csf2ra deletion attenuates acute lung injuries induced by intratracheal inoculation of aerosolized ricin in mice
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ABSTRACT:
PROVIDER: PRJNA820831 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18506502_1.fastq.gz | Fastqsanger.gz | |||
| SRR18506502_2.fastq.gz | Fastqsanger.gz | |||
| SRR18506503_1.fastq.gz | Fastqsanger.gz | |||
| SRR18506503_2.fastq.gz | Fastqsanger.gz | |||
| SRR18506504_1.fastq.gz | Fastqsanger.gz |
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Project description:The global transcriptome profile of lung tissue in WT and Csf2ra knockout mice after exposure to aerosolized ricin
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Project description:Specific therapeutics are not available for acute lung injury (ALI) induced by ricin toxin (RT). Inhibiting the host immune response in the course of pulmonary ricinosis is hypothesized to be of benefit and can be achieved by impairing granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, thereby reducing the pro-inflammatory response to exogenous foreign body invasion. However, it is unknown whether mice with impaired GM-CSF signaling can survive after RT inhalation. To test this, colony stimulating factor 2 receptor alpha (Csf2ra) knockout (KO) mice that lack GM-CSF signaling and wild-type (WT) mice models of intratracheal exposure to a lethal dose (2× LD50) of RT were established. Survival was greater in Csf2ra KO mice 21 days after RT inhalation compared with WT mice. Highly co-expressed genes that probably attenuated the pro-inflammatory response in the lung of Csf2ra KO mice were identified. Bioinformatics analysis revealed that transcriptome changes involved mostly inflammation-related genes after RT exposure in both Csf2ra KO mice and WT mice. However, the activity levels of pro-inflammatory pathways, such as the TNF signaling pathway and NF-κB signaling pathway, in Csf2ra KO mice were significantly decreased and the degree of neutrophil chemotaxis and recruitment inhibited after RT-exposure relative to WT mice. RT-qPCR and flow cytometry validated results of RNA-Seq analysis. This work provides potential avenues for host-directed therapeutic applications that can mitigate the severity of ALI-induced by RT.
| S-EPMC9531258 | biostudies-literature
Project description:Ricin is a potential bioweapon because of its toxicity, availability, and ease of production. When delivered to the lungs, ricin causes severe pulmonary damage with symptoms that are similar to those observed in acute lung injury and adult respiratory distress syndrome. The airway epithelium plays an important role in the pathogenesis of many lung diseases, but its role in ricin intoxication has not been elucidated. Exposure of cultured primary human airway epithelial cells to ricin resulted in the activation of stress-activated protein kinases (SAPKs) and NF-κB and in the increased expression of multiple proinflammatory molecules. Among the genes upregulated by ricin and identified by microarray analysis were those associated with transcription, nucleosome assembly, inflammation, and response to stress. Sequence analysis of the promoters of these genes identified NF-κB as one of the transcription factors whose binding sites were over-represented. Although airway cells secrete TNF-α in response to ricin, blocking TNF-α did not prevent ricin-induced activation of NF-κB. Inhibition of p38 MAPK by a chemical inhibitor and NF-κB by short interfering RNA resulted in a marked reduction in the expression of proinflammatory genes, demonstrating the importance of these two pathways in ricin intoxication. Therefore, the p38 MAPK and NF-κB pathways are potential therapeutic targets for reducing the inflammatory consequences of ricin poisoning. Experiment Overall Design: Control RNA from untreated primary human airway cells was compared to RNA from ricin-treated airway cells
2008-06-15 | E-GEOD-7845 | biostudies-arrayexpress
Project description:Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, is generally known to be the most poisonous of all biological toxins. In this study, we evaluate the protection conferred by intratracheal (i.t.) inoculation immunization with recombinant Hc subunit (AHc) vaccines against aerosolized BoNT/A intoxication. Three AHc vaccine formulations, i.e., conventional liquid, dry powder produced by spray freeze drying, and AHc dry powder reconstituted in water are prepared, and mice are immunized via i.t. inoculation or subcutaneous (s.c.) injection. Compared with s.c.-AHc-immunized mice, i.t.-AHc-immunized mice exhibit a slightly stronger protection against a challenge with 30,000× LD50 aerosolized BoNT/A. Of note, only i.t.-AHc induces a significantly higher level of toxin-neutralizing mucosal secretory IgA (SIgA) production in the bronchoalveolar lavage of mice. In conclusion, our study demonstrates that the immune protection conferred by the three formulations of AHc is comparable, while i.t. immunization of AHc is superior to s.c. immunization against aerosolized BoNT/A intoxication.
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Project description:The goal of this study is to explore the alterations in gene expression in lungs of mice 48 hours after exposure to low-dose ricin compared to lungs of naive mice, in order to provide a framework for comparative investigation of genes and mechanisms that may contribute to the developing lung disease. Methods: Total RNA was extracted from lungs of naive or ricin intoxicated mice (intranasally exposure to 1.7 µg/kg ricin), using the RNeasy mini kit (Qiagen). RNA-seq libraries were constructed and sequencing of 100bp paired-end was performed on the Illumina NovaSeq 6000 system. Sequencing yielded about 21M reads per sample that were mapped to the mouse genome. The expression of the infected sample was compared to mock sample, and RNA ratios were clustered using partitioning clustering. We next carried out GO term enrichment analysis. Results: Principal component analysis revealed distinct transcriptional signatures between naïve and ricin mice. We found 8545 differentially expressed genes in the ricin group, including 4394 upregulated and 4151 downregulated genes.
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Project description:Ricin is a potential bioweapon because of its toxicity, availability, and ease of production. When delivered to the lungs, ricin causes severe pulmonary damage with symptoms that are similar to those observed in acute lung injury and adult respiratory distress syndrome. The airway epithelium plays an important role in the pathogenesis of many lung diseases, but its role in ricin intoxication has not been elucidated. Exposure of cultured primary human airway epithelial cells to ricin resulted in the activation of stress-activated protein kinases (SAPKs) and NF-κB and in the increased expression of multiple proinflammatory molecules. Among the genes upregulated by ricin and identified by microarray analysis were those associated with transcription, nucleosome assembly, inflammation, and response to stress. Sequence analysis of the promoters of these genes identified NF-κB as one of the transcription factors whose binding sites were over-represented. Although airway cells secrete TNF-α in response to ricin, blocking TNF-α did not prevent ricin-induced activation of NF-κB. Inhibition of p38 MAPK by a chemical inhibitor and NF-κB by short interfering RNA resulted in a marked reduction in the expression of proinflammatory genes, demonstrating the importance of these two pathways in ricin intoxication. Therefore, the p38 MAPK and NF-κB pathways are potential therapeutic targets for reducing the inflammatory consequences of ricin poisoning. Keywords: Comparative genomic hybridization
2007-05-22 | GSE7845 | GEO
Project description:The toxin ricin has been shown to cause inflammatory lung damage, leading to pulmonary oedema and, at higher doses, mortality. In order to understand the genetic basis of this inflammatory cascade a custom microarray platform (1509 genes) directed towards immune and inflammatory markers was used to investigate the temporal expression profiles of genes in a Balb/c mouse model of inhalational ricin exposure. To facilitate examination of those genes involved in both inflammatory cascades and wound repair the dose which was investigated was sub-lethal across a 96 hour time course. Histopathology of the lung was mapped across the time course and genetic responses considered in the context of overall lung pathology. 685 genes were found to be statistically significantly different compared to controls, across the time course and these genes have been investigated in the context of their biological function in ricin poisoning. As well as confirming key inflammatory markers associated with ricin intoxication (TNFa and Il1b) several pathways that are altered in expression were identified following pulmonary exposure to ricin. These genes included those involved in cytokine-cytokine signalling cascades (IL1, IL1r, IL1r2, Ccl 4, 6, 10), focal adhesion (Fn1, ICAM1) and tissue remodelling (VEGF, Pim1). Furthermore, the observed alteration in expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) indicates a key role in membrane integrity and cellular adhesion in ricin poisoning. Data captured using this transcriptomic approach could be used to develop a specific approach to the treatment of inhalational ricin exposure. This work was conducted as part of a wider programme of work to compare a number of militarily relevant lung damaging agents, with a view to establishing a rational basis for the identification of more generic medical countermeasures. Four groups of six mice were exposed to ricin and a further groups exposed to vehicle only control (PBS). Following exposure mice were culled at 6 timepoints (1, 4, 7, 24, 48 and 96h). RNA was extracted and run on the custom array.
2009-08-19 | E-GEOD-17431 | biostudies-arrayexpress
Project description:Hypervirulent Klebsiella pneumoniae (hvKp) can cause life-threatening community-acquired infections among healthy young individuals and is thus of concern for global dissemination. In this study, a mouse model of acute primary hvKp pneumonia was established via aerosolized intratracheal (i.t.) inoculation, laying the foundation for conducting extensive studies related to hvKp. Subsequently, a time-course transcriptional profile was created of the lungs from the mouse model at 0, 12, 24, 48 and 60 hours post-infection (hpi) using RNA Sequencing (RNA-Seq). RNA-Seq data were analyzed with the use of Mfuzz time clustering, weighted gene co-expression network analysis (WGCNA) and Immune Cell Abundance Identifier for mouse (ImmuCellAI-mouse). A gradual change in the transcriptional profile of the lungs was observed that reflected expected disease progression. At 12 hpi, genes related to acute phase inflammatory response increased in expression and lipid metabolism appeared to have a pro-inflammatory effect. At 24 hpi, exacerbation of inflammation was observed and active IFN-γ suggested that signaling promoted activation and recruitment of macrophages occurred. Genes related to maintaining the structural integrity of lung tissues showed a sustained decrease in expression after infection and the decrease was especially marked at 48 hpi. TNF, IL-17, MAPK and NF-kB signaling pathways may play key roles in the immunopathogenesis mechanism at all stages of infection. Natural killer (NK) cells consistently decreased in abundance after infection, which has rarely been reported in hvKp infection and could provide a new target for treatment. Genes Saa1 and Slpi were significantly upregulated during infection. Both Saa1, which is associated with lipopolysaccharide (LPS) that elicits host inflammatory response, and Slpi, which encodes an antimicrobial protein, have not previously been reported in hvKp infections and could be important targets for subsequent studies. To t our knowledge, this paper represents the first study to investigate the pulmonary transcriptional response to hvKp infection. The results provide new insights into the molecular mechanisms underlying the pathogenesis of hvKp pulmonary infection that can contribute to the development of therapies to reduce hvKp pneumonia.
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Project description:The toxin ricin has been shown to cause inflammatory lung damage, leading to pulmonary oedema and, at higher doses, mortality. In order to understand the genetic basis of this inflammatory cascade a custom microarray platform (1509 genes) directed towards immune and inflammatory markers was used to investigate the temporal expression profiles of genes in a Balb/c mouse model of inhalational ricin exposure. To facilitate examination of those genes involved in both inflammatory cascades and wound repair the dose which was investigated was sub-lethal across a 96 hour time course. Histopathology of the lung was mapped across the time course and genetic responses considered in the context of overall lung pathology. 685 genes were found to be statistically significantly different compared to controls, across the time course and these genes have been investigated in the context of their biological function in ricin poisoning. As well as confirming key inflammatory markers associated with ricin intoxication (TNFa and Il1b) several pathways that are altered in expression were identified following pulmonary exposure to ricin. These genes included those involved in cytokine-cytokine signalling cascades (IL1, IL1r, IL1r2, Ccl 4, 6, 10), focal adhesion (Fn1, ICAM1) and tissue remodelling (VEGF, Pim1). Furthermore, the observed alteration in expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) indicates a key role in membrane integrity and cellular adhesion in ricin poisoning. Data captured using this transcriptomic approach could be used to develop a specific approach to the treatment of inhalational ricin exposure. This work was conducted as part of a wider programme of work to compare a number of militarily relevant lung damaging agents, with a view to establishing a rational basis for the identification of more generic medical countermeasures.
2009-08-19 | GSE17431 | GEO
Project description:The toxic protein ricin (also known as RCA60), found in the seed of the castor plant (Ricinus communis) is frequently encountered in law enforcement investigations. The ability to detect ricin by analyzing its proteolytic (tryptic) peptides by liquid chromatography-tandem mass spectrometry (LC-MS/MS) is well established. However, ricin is just one member of a family of proteins in R. communis with closely related amino acid sequences, including R. communis agglutinin I (RCA120) and other ricin-like proteins (RLPs). Inferring the presence of ricin from its constituent peptides requires an understanding of the specificity, or uniqueness to ricin, of each peptide. Here we describe the set of ricin-derived tryptic peptides that can serve to uniquely identify ricin in distinction to closely-related RLPs and to proteins from other species. Other ricin-derived peptide sequences occur only in the castor plant, and still others are shared with unrelated species. We also characterized the occurrence and relative abundance of ricin and related proteins in an assortment of forensically relevant crude castor seed preparations. We find that whereas ricin and RCA120 are abundant in castor seed extracts, other RLPs are not represented by abundant unique peptides. Therefore, the detection of peptides shared between ricin and RLPs (other than RCA120) in crude castor seed extracts most likely reflects the presence of ricin in the sample.
2017-10-17 | PXD007933 | Pride