Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effect of PI3Kgamma inhibition on inflammation in a mouse model of COVID-19

ABSTRACT: SARS-CoV-2 infections induce aberrant pulmonary and systemic inflammation, vascular leak, coagulation and fatal organ damage. To identify therapeutic strategies to suppress COVID-19-associated inflammation, we sequenced lung tissue from sham infected mice and mice infected with SARS-CoV-2 that were treated with the cancer therapeutic IPI-549 (eganelisib) or vehicle. IPI-549 suppressed signatuers of pulmonary inflammation and reduced signatures of lung damage. These studies demonstrate the essential role of myeloid cells and PI3Kγ in SARS-CoV-2 inflammatory disease and support the use of myeloid cell inhibitors such as IPI-549 to suppress inflammation and promote survival in pulmonary infections like SARS-CoV-2.

ORGANISM(S): Mus musculus

PROVIDER: GSE229570 | GEO | 2023/04/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

PI3Kg inhibition circumvents inflammation and mortality in SARS-CoV-2 and other infections

Project description:Virulent infectious agents such as SARS-CoV-2 and Methicillin Resistant Staphylococcus Aureus (MRSA) induce tissue damage that recruits neutrophils and monocyte/macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2 infected lungs, express phosphatidylinositol 3-kinase gamma (PI3K a signaling protein that coordinately controls granulocyte and monocyte trafficking to diseased tissues and immune suppressive, pro-fibrotic transcription in myeloid cells. PI3K deletion and inhibition with the clinical PI3K inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage and cytokine storm. These results demonstrate essential roles for PI3K in inflammatory lung disease and support the potential use of PI3K inhibitors to suppress inflammation in severe infectious diseases.

2024-03-12 | GSE255211 | GEO

Main Postoperative Complications After COVID-19

Project description:To explore the relationship between SARS-CoV-2 infection in different time before operation and postoperative main complications (mortality, main pulmonary and cardiovascular complications) 30 days after operation; To determine the best timing of surgery after SARS-CoV-2 infection.

| 5792 | ecrin-mdr-crc

A Retrospective Cohort Study for Main Postoperative Complications After SARS-CoV-2 Infection

| 12454 | ecrin-mdr-crc

Bulk RNA Barcoding and sequencing (BRB-seq) of Mock, SARS-CoV, and SARS-CoV-2 infected human airway epithelial cell cultures at 33°C and 37°C

Project description:For the assessment of host response dynamics to SARS-CoV and SARS-CoV-2 infections in human airway epithelial cells at ambient temperature corresponding to the upper or lower respiratory tract. We performed a temporal transcriptome analysis on human airway epithelial cell (hAEC) cultures infected with SARS-CoV and SARS-CoV-2, as well as uninfected hAEC cultures, incubated either at 33°C or 37°C. hAEC cultures were harvested at 24, 48 72, 96 hpi and processed for Bulk RNA Barcoding and sequencing (BRB-seq), which allows a rapid and sensitive genome-wide transcriptomic analysis in a highly multiplexed manner. Transcriptome data was obtained from a total of 7 biological donors for pairwise comparisons of SARS-CoV or SARS-CoV-2 virus-infected to unexposed hAEC cultures at respective time points and temperatures.

2020-11-27 | E-MTAB-9781 | biostudies-arrayexpress

The PDZ-binding motif of SARS-CoV envelope protein is a determinant of viral pathogenesis

Project description:A recombinant SARS-CoV lacking the envelope (E) protein is attenuated in vivo. Here we report that E protein PDZ-binding motif (PBM), a domain involved in protein-protein interactions, is a major virulence determinant in vivo. Elimination of SARS-CoV E protein PBM by using reverse genetics led to attenuated viruses (SARS-CoV-mutPBM) and to a reduction in the deleterious exacerbate immune response triggered during infection with the parental virus (SARS-CoV-wt). Cellular protein syntenin bound E protein PBM during SARS-CoV infection. Syntenin activates p38 MAPK leading to overexpression of inflammatory cytokines, and we have shown that active p38 MAPK was reduced in lungs of mice infected with SARS-CoVs lacking E protein PBM (SARS-CoV-mutPBM) as compared with the parental virus (SARS-CoV-wt), leading to a decreased expression of inflammatory cytokines and to viral attenuation. Therefore, E protein PBM is a virulence factor that activates pathogenic immune response most likely by using syntenin as a mediator of p38 MAPK induced inflammation. Three biological replicates were independently hybridized (one channel per slide) for each sample type (SARS-CoV-wt, SARS-CoV-mutPBM, Mock). Slides were Sure Print G3 Agilent 8x60K Mouse (G4852A-028005)

2014-10-31 | E-GEOD-52920 | biostudies-arrayexpress

Contribution of host miRNA-223-3p to SARS-CoV-induced lung inflammatory pathology

Project description:Severe acute respiratory syndrome coronavirus (SARS-CoV) and the closely related SARS-CoV-2 are emergent highly pathogenic human respiratory viruses causing acute lethal disease associated with lung damage and dysregulated inflammatory responses. SARS-CoV envelope protein (E) is a virulence factor involved in the activation of various inflammatory pathways. Here, we study the contribution of host miRNAs to the virulence mediated by E protein. Small RNAseq analysis of infected mouse lungs identified miRNA-223 as a potential regulator of pulmonary inflammation, since it was significantly increased in SARS-CoV-WT virulent infection as compared to the attenuated SARS-CoV-∆E infection. In vivo inhibition of miRNA-223-3p increased mRNA levels of pro-inflammatory cytokines and NLRP3 inflammasome, suggesting that during lung infection, miRNA-223 might contribute to restrict an excessive inflammatory response. Interestingly, miRNA-223-3p inhibition also increased the levels of the CFTR transporter, which is involved in edema resolution and was significantly downregulated in the lungs of mice infected with the virulent SARS-CoV-WT virus. At the histopathological level, a decrease in the pulmonary edema was observed when miR-223-3p was inhibited, suggesting that miRNA-223-3p was involved in the regulation of the SARS-CoV-induced inflammatory pathology. These results indicate that miRNA-223 participates in the regulation of E protein mediated- inflammatory response during SARS-CoV infection by targeting different host mRNAs involved in the pulmonary inflammation and identify miRNA-223 as a potential therapeutic target in SARS-CoV infection.

2022-02-04 | GSE180563 | GEO

SM003 - icSARS CoV, SARS MA15 wild type and SARS BatSRBD mutant virus infections of C57BL6 mice - A time course

Project description:The purpose of this experiment was to investigate the transcriptional differences between mice infected with icSARS CoV, SARS MA15 wild type or SARS BatSRBD viruses. Overview of Experiment: Groups of 20 week old C57BL6 mice were infected with icSARS CoV, Wild Type SARS MA15 or SARS BatSRBD mutant viruses. Infections were done at 10^4 PFU or 10^5 PFU or time-matched mock infected. Time points were 1, 2, 4 and 7 d.p.i. There were 3-5 animals/dose/time point. Lung samples were collected for virus load, transcriptional and proteomics analysis. Weight loss and animal survival were also monitored.

2014-02-15 | E-GEOD-50000 | biostudies-arrayexpress

Targeting PI3Kgamma dependency in leukemia treatment [PI3Kgamma inhibition]

Project description:Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.

2024-03-18 | GSE243654 | GEO

Differences in syncytia formation by SARS-CoV-2 variants modify host chromatin accessibility and cellular senescence via TP53 [RNA-Seq]

Project description:COVID-19 remains a significant public health threat due to the ability of SARS-CoV-2 variants to evade the immune system and cause breakthrough infections. Although pathogenic coronaviruses such as SARS-CoV-2 and MERS-CoV lead to severe respiratory infections, how these viruses affect the chromatin proteomic composition upon infection remains largely uncharacterized. Here we used our recently developed integrative DNA And Protein Tagging (iDAPT) methodology to identify changes in host chromatin accessibility states and chromatin proteomic composition upon infection with pathogenic coronaviruses. SARS-CoV-2 infection induces TP53 stabilization on chromatin, which contributes to its host cytopathic effect. We mapped this TP53 stabilization to the SARS-CoV-2 spike and its propensity to form syncytia, a consequence of cell-cell fusion. Differences in SARS-CoV-2 spike variant-induced syncytia formation modify chromatin accessibility, cellular senescence, and inflammatory cytokine release via TP53. Our findings suggest that differences in syncytia formation alter senescence-associated inflammation, which varies among SARS-CoV-2 variants.

2023-09-30 | GSE241891 | GEO