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Host lipidome analysis during rhinovirus replication in HBECs identifies potential therapeutic targets.

ABSTRACT: In patients with asthma or chronic obstructive pulmonary disease, rhinovirus (RV) infections can provoke acute worsening of disease, and limited treatment options exist. Viral replication in the host cell induces significant remodeling of intracellular membranes, but few studies have explored this mechanistically or as a therapeutic opportunity. We performed unbiased lipidomic analysis on human bronchial epithelial cells infected over a 6 h period with the RV-A1b strain of RV to determine changes in 493 distinct lipid species. Through pathway and network analysis, we identified temporal changes in the apparent activities of a number of lipid metabolizing and signaling enzymes. In particular, analysis highlighted FA synthesis and ceramide metabolism as potential anti-rhinoviral targets. To validate the importance of these enzymes in viral replication, we explored the effects of commercially available enzyme inhibitors upon RV-A1b infection and replication. Ceranib-1, D609, and C75 were the most potent inhibitors, which confirmed that FAS and ceramidase are potential inhibitory targets in rhinoviral infections. More broadly, this study demonstrates the potential of lipidomics and pathway analysis to identify novel targets to treat human disorders.

SUBMITTER: Nguyen A

PROVIDER: S-EPMC6121942 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Host lipidome analysis during rhinovirus replication in HBECs identifies potential therapeutic targets.

Nguyen An A Guedán Anabel A Mousnier Aurelie A Swieboda Dawid D Zhang Qifeng Q Horkai Dorottya D Le Novere Nicolas N Solari Roberto R Wakelam Michael J O MJO

Journal of lipid research 20180626 9

In patients with asthma or chronic obstructive pulmonary disease, rhinovirus (RV) infections can provoke acute worsening of disease, and limited treatment options exist. Viral replication in the host cell induces significant remodeling of intracellular membranes, but few studies have explored this mechanistically or as a therapeutic opportunity. We performed unbiased lipidomic analysis on human bronchial epithelial cells infected over a 6 h period with the RV-A1b strain of RV to determine change ...[more]

PMID: 29946055

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Project description:BackgroundCardiopulmonary bypass (CPB) causes systemic inflammation during pediatric cardiac surgery, which can contribute to post-operative organ dysfunction and prolonged recovery. This study aims to identify key inflammatory mediators related to this clinically significant immunologic response.MethodsPediatric patients were enrolled in a single-arm prospective clinical study (NCT05154864) and received standard cardiac operation, CPB and subzero-balance ultrafiltration. Arterial samples were taken before CPB initiation and immediately after weaning, and concentrations of 33 inflammatory mediators were assayed. A principal component analysis with hierarchical clustering (PCA-HCPC) included inflammatory mediator concentrations measured at the end of CPB, validated peak post-operative clinical scores, ventilation time and intensive care length of stay. Mahalanobis distance assessed statistical differences between clusters. Spearman's correlation described the linear relationship between mediator concentrations at the end of CPB and intensive care length of stay. Results are median (IQR).ResultsForty consecutive patients were enrolled; the majority were male (58%), age of 7.3 (1.7-39.0) months and weight of 6.7 (4.6-14.9) kg. The PCA-HCPC revealed activated complement factors along with all peak clinical scores and prolonged intensive care requirements in the same cluster. Cytokine, chemokine, and leukocyte adhesion molecule concentrations were found in two other distinct clusters (Mahalanobis distance = 16.5; p = 0.004 and Mahalanobis distance = 17.4; p = 5.8 × 10-4). Mediator concentrations of C2 (Rho = 0.50; p = 0.001), C3 (Rho = 0.58; p = 1.1 × 10-4), C3b (Rho = 0.47; p = 0.002), C5 (Rho = 0.48; p = 0.002) and C5a (Rho = 0.63; 1.7 × 10-5) showed linear correlations with intensive care unit length of stay.ConclusionsActivated complement factors, but not pro-inflammatory cytokines or chemokines, were most related to cardiopulmonary dysfunction and prolonged recovery in this novel analysis. Investigation of therapies that inhibit complement to dampen CPB-associated inflammation and enhance recovery after pediatric cardiac surgery is warranted. Trial Registration ClinicalTrials.gov, NCT05154864.

Project description:BackgroundSepsis and septic shock are life-threatening diseases with high mortality rate in intensive care unit (ICU). Acute kidney injury (AKI) is a common complication of sepsis, and its occurrence is a poor prognostic sign to septic patients. We analyzed co-differentially expressed genes (co-DEGs) to explore relationships between septic shock and AKI and reveal potential biomarkers and therapeutic targets of septic-shock-associated AKI (SSAKI).MethodsTwo gene expression datasets (GSE30718 and GSE57065) were downloaded from the Gene Expression Omnibus (GEO). The GSE57065 dataset included 28 septic shock patients and 25 healthy volunteers and blood samples were collected within 0.5, 24 and 48 h after shock. Specimens of GSE30718 were collected from 26 patients with AKI and 11 control patents. AKI-DEGs and septic-shock-DEGs were identified using the two datasets. Subsequently, Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs. We also evaluated co-DEGs and corresponding predicted miRNAs involved in septic shock and AKI.ResultsWe identified 62 DEGs in AKI specimens and 888, 870, and 717 DEGs in septic shock blood samples within 0.5, 24 and 48 h, respectively. The hub genes of EGF and OLFM4 may be involved in AKI and QPCT, CKAP4, PRKCQ, PLAC8, PRC1, BCL9L, ATP11B, KLHL2, LDLRAP1, NDUFAF1, IFIT2, CSF1R, HGF, NRN1, GZMB, and STAT4 may be associated with septic shock. Besides, co-DEGs of VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 coupled with corresponding predicted miRNAs, especially miR-29b-3p, miR-152-3p, and miR-223-3p may be regarded as promising targets for the diagnosis and treatment of SSAKI in the future.ConclusionsSeptic shock and AKI are related and VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 genes are significantly associated with novel biomarkers involved in the occurrence and development of SSAKI.

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Host lipidome analysis during rhinovirus replication in HBECs identifies potential therapeutic targets.

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Host lipidome analysis during rhinovirus replication in HBECs identifies potential therapeutic targets.

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