Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE255211 | GEO | 2024/03/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Project description: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.

2023-04-30 | GSE229570 | GEO

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

Gene Expression Analysis of Host Immune Responses in CD11b positive cells isolated from lungs of the UV inactivated SARS-CoV-immunized mice following Lethal SARS-CoV Infection

Project description:To better understand the biological pathways by which UV inactivated SARS-CoV-induced pulmonary eosinophilia occurs, we examined global transcriptional changes in macrophages from the lungs of mouse. Female BALB/c mice were used at 21 weeks of age. Mice were subcutaneously immunized with UV inactivated SARS-CoV (UV-V) or UV-V and Toll like receptor (TLR) ligands at 6 and 1 weeks prior to mouse-adapted SARS-CoV (n=6 per group). Mice were intranasally challenged with 1E+6 TCID50 in 30M-NM-<L. MEM was challenged in six mice as control infection. Mice were sacrificed and collected lungs at 1 days after challenge, then CD11b positive cells were isolated from the lungs of these mice. These cells were used for the analysis of microarray.

2014-05-22 | E-GEOD-50855 | biostudies-arrayexpress

Caspase-11 promotes inflammation and thrombosis in SARS-CoV-2 infection

Project description:SARS-CoV-2 infections are a worldwide health concern, and new treatment strategies are needed for decreasing virus-induced inflammatory tissue damage. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive. Here, we show that the innate immunity proteins, human caspase-4 (CASP4), and its mouse homologue, caspase-11 (CASP11), are upregulated in SARS-CoV-2 infections, and that CASP4 expression correlates with severity of SARS-CoV-2 infection in humans. SARS-CoV-2-infected Casp11-/- mice experienced less severe infections in terms of weight loss and lung damage than WT mice. Notably, these phenotypes were not recapitulated in mice lacking the CASP11 downstream effector gasdermin D (Gsdmd-/-), though viral titers were similar in all groups. Global transcriptomics of infected WT and Casp11-/- lungs identified decreased inflammation and neutrophil gene signatures. We confirmed that protein levels of inflammatory mediators IL-1β and CXCL1, and neutrophil infiltration, were decreased in Casp11-/- lungs. Additionally, Casp11-/- lungs expressed less von Willebrand factor, a marker for endothelial dysfunction and more Kruppel-Like Factor 2 (KLF2), a transcription factor with anti-thrombotic functions. Thus, CASP11 is established as an upstream regulator of blood coagulopathy in SARS-CoV-2 infection. Overall, our results demonstrate that CASP11, promotes detrimental SARS-CoV-2-associated inflammation and coagulopathy, identifying CASP11 as a promising drug target for treatment and prevention of tissue damage in COVID-19.

2023-02-16 | GSE184678 | GEO

Spatiotemporal analysis of SARS-CoV-2 infection in hamster lungs reveals an expansive wave of monocyte-derived macrophages associated with vascular damage and virus clearance

Project description:Characteristics of the innate immune response to SARS-CoV-2 in the lungs are pivotal for the ability of the organism to deal with infection. Excessive infiltration of macrophages is associated with poor disease outcome. Using 3D spatiotemporal analysis of optically clear hamster lung tissues in combination with virological, immunohistochemical and RNA sequence analyses we show the spread of SARS-CoV-2 through the lungs and rapid anti-viral response in infected lung epithelial cells, followed by a synchronized wave of CD68+ monocyte-derived macrophage (MDM) infiltration leading to virus elimination from the tissue. The SARS-CoV-2 induced innate immune processes are closely related with the onset of necrotic and lung remodelling responses in the lungs, which is manifested in extensive apoptosis, vascular damage, thrombosis, and an early initiation of cell proliferation. Here we show that MDM are directly linked to the virus clearance, and these cells appear in connection with tissue injury and blood vessel rupture. Rapid initiation of prothrombotic factor upregulation, tissue repair and alveolar cell proliferation results in tissue remodelling, which is followed by lung fibrosis development despite decrease in the inflammatory and anti-viral activities. Thus, although the animals are able to resolve the infection and repair lung tissue integrity, longer term structural changes in lungs indicate that the efficient balance between tissue damage and repair is critical for successful lung function restoration.

2023-02-20 | GSE225382 | GEO

Comparative Pathogenesis of Three Human and Zoonotic SARS-CoV Strains in Cynomolgus Macaques

Project description:The severe acute respiratory syndrome (SARS) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. SARS-CoV is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. To prevent future introductions of zoonotic SARS-CoV strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both late human and zoonotic isolates. Here we show that both human and zoonotic SARS-CoV strains can infect cynomolgus macaques and resulted in radiological as well as histopathological changes similar to those seen in mild human cases. Viral replication was higher in animals infected with a late human phase isolate compared to a zoonotic isolate. Host responses to the three SARS-CoV strains were similar and only apparent early during infection with the majority of genes associated with interferon signalling pathways.This study characterizes critical disease models in the evaluation and licensure of therapeutic strategies against SARS-CoV for human use 4 strains, time course, lungs

2011-08-31 | E-GEOD-23955 | biostudies-arrayexpress

CCR2-dependent monocyte-derived cells restrict SARS-CoV-2 infection

Project description:SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19) and current evidence suggests severe disease is associated with dysregulated immunity within the respiratory tract1,2. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2-dependent infiltration of monocytes restricts viral burden in the lung. We find that a recently developed mouse-adapted MA-SARS-CoV-2 strain, as well as the emerging B.1.351 variant, trigger an inflammatory response in the lung characterized by expression of pro-inflammatory cytokines and interferon-stimulated genes. Using intravital antibody labeling, we demonstrate that MA-SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45+ cells into the lung parenchyma that is dominated by monocyte-derived cells. scRNA-seq analysis of lung homogenates identified a hyper-inflammatory monocyte profile. We utilize this model to demonstrate that mechanistically, CCR2 signaling promotes infiltration of classical monocytes into the lung and expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified a CCR2-monocyte axis that is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection.

2021-10-23 | GSE186360 | GEO

Senescent endothelial cells are predisposed to SARS-CoV-2 infection and subsequent endothelial dysfunction

Project description:The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains to spread worldwide. COVID-19 is characterized by the striking high mortality in elderly; however, its mechanistic insights remain unclear. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Here, we experimentally investigated the SARS-CoV-2 infection in cultured human ECs, and performed a comparative analysis for post-infection molecular events using early passage and replicative senescent ECs. We found that; 1) SARS-CoV-2 infects ECs but does not replicate and disappears in 72 hours without causing severe cell damage, 2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, 3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, 4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in early passage ECs, which might causes further exacerbated dysfunction in senescent ECs. These data suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.

2023-05-01 | GSE206677 | GEO

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

SM001: SARS CoV MA15 infection of C57Bl/6 mouse model – Data from 4 viral doses at 1, 2, 4 and 7 days post infection.

Project description:Purpose of experiment was to perform transcriptomic analysis on C57Bl/6 mice infected with different doses of SARS CoV MA15 at 4 different days post infection. Twenty-week-old C57BL/6 mice were infected by intranasal instillation of 10^2, 10^3, 10^4 or 10^5 PFU of SARS CoV MA15 in 50 µl of PBS or mock-infected with PBS alone. At days 1, 2, 4 and 7 days post-infection, lungs were harvested and total RNA was isolated and subjected to microarray analysis. The experimental design was for 4- 5 mice/time point/dose and 3 time-matched mocks. The NIAID Systems Virology Center

2011-11-01 | E-GEOD-33266 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data