Summary of Study ST003290

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002042. The data can be accessed directly via it's Project DOI: 10.21228/M8NV6P This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST003290
Study TitleHigh expression of oleoyl-ACP-hydrolase underpins life-threatening respiratory viral diseases
Study SummaryAlthough respiratory viral infections cause significant morbidity and mortality, it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning hypercytokinemia and fatal disease. Our transcriptomics studies identified differential expression of 10 early host genes, defined by 16 probe sets, between patients who recovered and died. Seven probe sets were specific for the same host gene encoding for a key enzyme mediating free fatty acid production, oleoyl-ACP-hydrolase (OLAH). High OLAH levels in fatal A(H7N9) patients were detected early after hospital admission and persisted until patients died. Conversely, patients who recovered had minimal OLAH expression throughout their hospital stay. High OLAH levels were also detected in patients hospitalized for severe infections with seasonal influenza virus, SARS-CoV-2, respiratory syncytial virus (RSV) and for multisystem inflammatory syndrome in children (MIS-C), while the main catalytic product of OLAH, oleic acid, was increased in hospitalized compared to ambulatory patients. Among healthy individuals and those with mild infections, however, OLAH was minimally detected. To understand how OLAH drives disease severity, we generated olah deficient mice. In contrast to wild-type mice, lethal influenza infection of olah-/- mice led to survival, milder disease, and markedly reduced lung viral loads, tissue damage, infection-driven pulmonary innate cell infiltration and inflammatory milieu. This phenotype was associated with differential lipid droplet dynamics, and reduced viral infection and inflammatory responses in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza infection of macrophages and their inflammatory potential. Increased infectivity in the presence of olah was dependent on lipid droplet usage. Our findings define how expression of the key host enzyme, OLAH, drives life-threatening inflammation associated with respiratory viruses and propose OLAH as a potential early target for diagnosis and treatment of patients with severe disease. 
Institute
Peter Doherty Institute for Infection and Immunity
Last NameChua
First NameBrendon
Address792 Elizabeth St, Melbourne VIC 3000
Emailbychua@unimelb.edu.au
Phone+61383441130
Submit Date2024-06-26
Raw Data AvailableYes
Raw Data File Type(s)mzML
Analysis Type DetailLC-MS
Release Date2024-08-22
Release Version1
Brendon Chua Brendon Chua
https://dx.doi.org/10.21228/M8NV6P
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Combined analysis:

Analysis ID AN005388 AN005389
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Thermo Vanquish Thermo Vanquish
Column Waters ACQUITY UPLC HSS T3 (150 x 1mm,1.8um) Waters ACQUITY UPLC HSS T3 (150 x 1mm,1.8um)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Fusion Tribrid Orbitrap Thermo Fusion Tribrid Orbitrap
Ion Mode POSITIVE NEGATIVE
Units pmol/mg lung tissue pmol/mg lung tissue

Chromatography:

Chromatography ID:CH004085
Chromatography Summary:Solvent A: 6/4 (v/v) acetonitrile/water with 5 uM medronic acid and 10 mM ammonium acetate; Solvent B: 9/1 (v/v) isopropanol/acetonitrile with 10 mM ammonium acetate
Instrument Name:Thermo Vanquish
Column Name:Waters ACQUITY UPLC HSS T3 (150 x 1mm,1.8um)
Column Temperature:50
Flow Gradient:[Time(min), %B solvent]: [0,3], [5,3], [10,70], [26,99], [29,99], [29.1,3], [33,3] 
Flow Rate:60 uL/min
Solvent A:60% acetonitrile/40% water; 5 uM medronic acid; 10 mM ammonium acetate
Solvent B:90% isopropyl alcohol/10% acetonitrile; 10 mM ammonium acetate
Chromatography Type:Reversed phase
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