Human Rhinovirus Infection of the Respiratory Tract Affects Sphingolipid Synthesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE189056 | GEO | 2021/11/20
REPOSITORIES: GEO
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Project description:Rhinovirus (RV) is the most prevalent human respiratory virus. Each year, RV infects billions of people and is responsible for at least half of all common colds, the most common illness of humans. RV infection also affects the morbidity of a range of respiratory illnesses, such as bronchiolitis, pneumonia, asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Despite its biological importance and public health significance, little is known about the genetic architecture of response to RV. To address this, we obtained genome-wide genotype and gene expression data in uninfected and RV-infected peripheral blood mononuclear cells (PBMCs) from 98 individuals. We characterized gene expression differences in response to RV infection and mapped expression quantitative trait loci (eQTLs) in both uninfected and RV-infected PBMCs.
2015-04-14 | GSE53543 | GEO
Project description:Clinically significant radiation-induced lung injury (RILI) is associated with significant morbidity and mortality and a common toxicity in patients administered thoracic radiotherapy. While the molecular etiology of RILI is poorly understood, we previously characterized a murine model of RILI in which alterations in lung endothelial barrier integrity surfaced as a potentially important pathobiologic event. In these studies, inhibition of HMG-CoA reductase activity (simvastatin) reduced murine RILI-associated lung inflammation and vascular leak and attenuated radiation-induced dysregulation of sphingolipid metabolic pathway genes identified by genome-wide lung gene expression profiling. In the present study, we test the hypothesis that sphingolipid signaling components serve as important modulators of RILI pathobiology and novel therapeutic targets. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to cumulative sphingosine-1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage (BAL) fluid and lung tissue following 25 Gy exposure (6 weeks). Moreover, genetically-engineered mice with either targeted deletion of SphK1 (SphK1-/-), or with reduced expression of selective members of the S1P receptor family (S1PR1+/-, S1PR2-/-, S1PR3-/-,), exhibited marked susceptibility to RILI-mediated lung inflammation. Finally, we assessed the efficacy of three potent vascular barrier-protective S1P analogues FTY720 (FTY), fTysiponate (fTyS) and SEW-2871 (SEW) in attenuating indices of RILI. The phosphonate analogue, fTyS, and to a lesser degree SEW, exhibited significant attenuation of RILI and RILI-induced gene dysregulation compared to control RILI-challenged mice (6 weeks). In contrast, FTY failed to significantly alter physiologic or genomic changes compared to RILI-challenged controls. Together, these results support the targeting of sphingolipid components as a novel and effective therapeutic strategy in RILI. Four mice were treated with PBS as a control. Three mice were treated with (S)-FTY-phosphonate (0.1mg/kg) as a drug control. Three mice were treated with SEW-2871 (0.1mg/kg) as a drug control. Three mice were treated with FTY720 (0.1mg/kg) as a drug control. Three mice were treated with administered radiation (25 Gy) alone. Three mice were treated with both administered radiation (25 Gy) and (S)-FTY-phosphonate (0.1mg/kg). Three mice were treated with both administered radiation (25 Gy) and SEW-2871 (0.1mg/kg). Three mice were treated with both administered radiation (25 Gy) and FTY720 (0.1mg/kg).
2010-11-17 | E-GEOD-25295 | biostudies-arrayexpress
Project description:Growing evidence correlated changes in bioactive sphingolipids, particularly sphingosine-1-phosphate (S1P) and ceramides, with coronary artery diseases. Furthermore, specific plasma ceramide species can predict major cardiovascular events. Dysfunction of the endothelium lining lesion-prone areas plays a pivotal role in the initiation and progression of atherosclerosis. Yet, how sphingolipid metabolism and signaling change and contribute to endothelial dysfunction and atherosclerosis remain poorly understood. By using a mouse model of coronary atherosclerosis, we demonstrated that hemodynamic stress induces an early metabolic rewiring of endothelial sphingolipid de novo biosynthesis favoring S1P signaling over ceramide as protective response. Furthermore, our data are paradigm shift from the current believe that ceramide accrual contributes to endothelial dysfunction. The de novo biosynthesis of sphingolipids is commenced by serine palmitoyltransferase (SPT), and is downregulated by NOGO-B, an ER membrane protein. We showed that Nogo-B is upregulated by hemodynamic stress in myocardial endothelial cells (EC) of ApoE-/- mice and is expressed in the endothelium lining coronary lesions in mice and human. We demonstrated that mice lacking Nogo-B specifically in EC (Nogo-A/BECKOApoE-/-) were resistant to coronary atherosclerosis development and progression, and mortality. Fibrous cap thickness was significantly increased in Nogo-A/BECKOApoE-/- mice and correlated with reduced necrotic core and macrophage infiltration. Mechanistically, the deletion of Nogo-B in EC sustained the rewiring of sphingolipid metabolism towards S1P, imparting an atheroprotective transcriptional signature that refrain coronary atherogenesis and its progression. These findings also set forth the foundation for sphingolipid-based therapeutics to reduce the treat this condition.
2024-02-12 | GSE254426 | GEO
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Project description:Human rhinovirus (RV) is a major risk factor for COPD and asthma exacerbations, but exploration of RV pathogenesis has been hampered by a lack of disease relevant model systems. We performed a detailed characterization of host mRNA responses to RV infection in human precision cut lung tissue ex vivo (comparing to previously published asthma and COPD studies) and explored the impact of antiviral treatment. Genomic analyses revealed that RV not only induced anti-viral immune responses but also triggered changes in epithelial cell-associated pathways. Strikingly, the RV response in PCLS was reflective of gene expression changes described previously in COPD and asthma patients. While RV-induced host immune responses were abrogated by rupintrivir, RV-triggered epithelial processes were largely refractory to antiviral treatment.
2021-09-01 | GSE137905 | GEO
Project description:Rhinovirus (RV) is the most prevalent human respiratory virus. Each year, RV infects billions of people and is responsible for at least half of all common colds, the most common illness of humans. RV infection also affects the morbidity of a range of respiratory illnesses, such as bronchiolitis, pneumonia, asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Despite its biological importance and public health significance, little is known about the genetic architecture of response to RV. To address this, we obtained genome-wide genotype and gene expression data in uninfected and RV-infected peripheral blood mononuclear cells (PBMCs) from 98 individuals. We characterized gene expression differences in response to RV infection and mapped expression quantitative trait loci (eQTLs) in both uninfected and RV-infected PBMCs. The study includes data from uninfected and rhinovirus-infected peripheral blood mononuclear cells (PBMCs) from 98 individuals. Twenty ml of blood was drawn from each participant. PBMCs were isolated from whole blood samples by Ficoll-Paque separation. From each subject, 4 million PBMCs were treated with media alone for 24 hours and 4 million PBMCs were treated with media containing RV16 for 24 hours. The multiplicity of infection was 10 plaque-forming units per cell. Total RNA was extracted after 24-hour incubation, using the RNeasy Plus Mini Kit; concentrations were measured on a Nanodrop ND-100 Spectrophotometer and quality was assessed using an Agilent 2100 Bioanalyzer. Genome wide gene expression profiling of uninfected and rhinovirus-infected PBMCs was obtained using Illumina HumanHT-12 v4 Expression BeadChip arrays at the University of Chicago Functional Genomics Core.
2015-04-14 | E-GEOD-53543 | biostudies-arrayexpress
Project description:Rhinoviruses (RVs) are major instigators of acute exacerbations of asthma, COPD and other respiratory diseases. RVs are categorized into three species (RV-A, RV-B, and RV-C), which comprise more than 160 serotypes, making it difficult to develop an effective vaccine. Currently no effective treatment for RV infection is available. Pulmonary surfactant is an extracellular complex of lipids and proteins that plays a central role in regulating innate immunity in the lung. The minor pulmonary surfactant lipids, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI), are potent regulators of inflammatory processes, and exert antiviral activity against respiratory syncytial virus (RSV) and influenza A viruses (IAV). In the current study, we examined the potencies of POPG and PI against rhinovirus A16 (RV-A16) in primary human airway epithelial cells (AECs) differentiated at an air-liquid interface (ALI). After AECs were infected with RV-A16, PI reduced viral RNA copy number by 80% and downregulated (55-65%) expression of antiviral genes (MDA5, IRF7 and IFN-lambda). In contrast, POPG only slightly decreased MDA5 (24%) and IRF7 (11%) gene expression but did not inhibit IFN-lambda gene expression or RV-A16 replication in AECs. However, both POPG and PI inhibited (50-80%) IL6 and CXCL11 gene expression and protein secretion. PI treatment dramatically attenuated global gene expression changes induced by RV-A16 infection in AECs. Cell type enrichment analysis of viral regulated genes opposed by PI treatment revealed that PI inhibited viral induction of goblet cell metaplasia and virus-induced downregulation of ciliated, club, and ionocyte cell types. Notably, PI treament altered the ability of RV-A16 to regulate expression of some phosphatidylinositol 4-kinase (PI4K), acyl-CoA binding domain containing (ACBD) and low density lipoprotein receptor (LDLR) genes that play critical roles in the formation and functioning of replication organelles (ROs) required for RV replication in host cells. These data suggest PI can be used as a potent, non-toxic antiviral agent for RV infection prophylaxis and treatment.
2023-04-04 | GSE226071 | GEO
Project description:Clinically significant radiation-induced lung injury (RILI) is associated with significant morbidity and mortality and a common toxicity in patients administered thoracic radiotherapy. While the molecular etiology of RILI is poorly understood, we previously characterized a murine model of RILI in which alterations in lung endothelial barrier integrity surfaced as a potentially important pathobiologic event. In these studies, inhibition of HMG-CoA reductase activity (simvastatin) reduced murine RILI-associated lung inflammation and vascular leak and attenuated radiation-induced dysregulation of sphingolipid metabolic pathway genes identified by genome-wide lung gene expression profiling. In the present study, we test the hypothesis that sphingolipid signaling components serve as important modulators of RILI pathobiology and novel therapeutic targets. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to cumulative sphingosine-1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage (BAL) fluid and lung tissue following 25 Gy exposure (6 weeks). Moreover, genetically-engineered mice with either targeted deletion of SphK1 (SphK1-/-), or with reduced expression of selective members of the S1P receptor family (S1PR1+/-, S1PR2-/-, S1PR3-/-,), exhibited marked susceptibility to RILI-mediated lung inflammation. Finally, we assessed the efficacy of three potent vascular barrier-protective S1P analogues FTY720 (FTY), fTysiponate (fTyS) and SEW-2871 (SEW) in attenuating indices of RILI. The phosphonate analogue, fTyS, and to a lesser degree SEW, exhibited significant attenuation of RILI and RILI-induced gene dysregulation compared to control RILI-challenged mice (6 weeks). In contrast, FTY failed to significantly alter physiologic or genomic changes compared to RILI-challenged controls. Together, these results support the targeting of sphingolipid components as a novel and effective therapeutic strategy in RILI.
2010-11-17 | GSE25295 | GEO
Project description:Human Rhinovirus Infection of the Respiratory Tract Affects Sphingolipid Synthesis
| PRJNA781263 | ENA
Project description:Hereditary sensory and autonomic neuropathy type I (HSAN-I) is neurological disorder characterized by distal sensory neuron dysfunction, frequent infections, and ulcerative mutilations. It remains unknown if HSAN-I directly dampens protective immunity. Here we report that HSAN-I-causing mutations of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) affect human T cell responses. T cell antigenic stimulation and inflammation induce SPTLC2 expression. Murine T cell-specific ablation of Sptlc2 fundamentally impairs antiviral T cell survival and effector function. Mechanistically, SPTLC2-deficiency reduces sphingolipid biosynthetic flux and causes a prolonged activation of the mechanistic target of rapamycin complex 1 (mTORC1), endoplasmic reticulum (ER) stress and CD8+ T cell death. Antiviral CD8+ T cell responses are restored by supplementing sphingolipids and pharmacologically inhibiting ER stress-induced cell death. Our study reveals that SPTLC2 underpins protective adaptive immunity by translating extracellular stimuli into intracellular anabolic signals and reducing cellular stress to maintain metabolic reprogramming sustainability
2019-04-02 | GSE112715 | GEO