Host-based lipid inflammation drives pathogenesis in
            <i>Francisella</i>
            infection

Scott, Alison; Post, Julia M.; Lerner, Robert G.; Ellis, Shane R.; Lieberman, Joshua A.; Shirey, Kari Ann; Heeren, Ron M. A.; Bîndilă, Laura; Ernst, Robert K.

doi:10.1073/pnas.1712887114

Cited by 37 publications

(56 citation statements)

References 53 publications

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“…The dual-polarity lipid imaging matrix, norharmane (NRM) 21,27 was prepared at 7 mg/mL in a solution of 2:1 chloroform:methanol (v:v). The NRM solution was applied using an HTX TM-sprayer (HTX Technologies, Chapel Hill, NC) using the following settings: 30 °C nozzle temperature, 10 passes, 0.120 mL/min flow rate, 1200 mm/min velocity, 3 mm track spacing, 10 psi pressure, 3 L/min gas flow, 30 s dry time between passes, using the “CC” coverage pattern.…”

Section: Methodsmentioning

confidence: 99%

Maintenance of Deep Lung Architecture and Automated Airway Segmentation for 3D Mass Spectrometry Imaging

Scott

Chandler

Ellis

et al. 2019

Sci Rep

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Mass spectrometry imaging (MSI) is a technique for mapping the spatial distributions of molecules in sectioned tissue. Histology-preserving tissue preparation methods are central to successful MSI studies. Common fixation methods, used to preserve tissue morphology, can result in artifacts in the resulting MSI experiment including delocalization of analytes, altered adduct profiles, and loss of key analytes due to irreversible cross-linking and diffusion. This is especially troublesome in lung and airway samples, in which histology and morphology is best interpreted from 3D reconstruction, requiring the large and small airways to remain inflated during analysis. Here, we developed an MSI-compatible inflation containing as few exogenous components as possible, forgoing perfusion, fixation, and addition of salt solutions upon inflation that resulted in an ungapped 3D molecular reconstruction through more than 300 microns. We characterized a series of polyunsaturated phospholipids (PUFA-PLs), specifically phosphatidylinositol (-PI) lipids linked to lethal inflammation in bacterial infection and mapped them in serial sections of inflated mouse lung. PUFA-PIs were identified using spatial lipidomics and determined to be determinant markers of major airway features using unsupervised hierarchical clustering. Deep lung architecture was preserved using this inflation approach and the resulting sections are compatible with multiple MSI modalities, automated interpretation software, and serial 3D reconstruction.

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Section: Methodsmentioning

confidence: 99%

Maintenance of Deep Lung Architecture and Automated Airway Segmentation for 3D Mass Spectrometry Imaging

Scott

Chandler

Ellis

et al. 2019

Sci Rep

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“…Matrix-assisted laser desorption/ionisation-mass spectrometry imaging (MALDI-MSI) is a powerful method for visualising the spatial distributions of lipids throughout biological tissues [1][2][3]. Its versatility for mapping changing lipid compositions within tissues has been demonstrated in a variety of applications, including oncology [4][5][6], bacterial infections [7,8] and liver disease [9,10], amongst many others. The heterogeneous lipid compositions observed with MSI are ultimately the result of cellular-level lipid metabolism occurring within the cells constituting the tissue sample.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of lipid coverage and high spatial resolution MALDI-imaging capabilities of oversampling combined with laser post-ionisation

et al. 2019

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Matrix-assisted laser desorption/ionisation-mass spectrometry imaging (MALDI-MSI) is a powerful technique for visualising the spatial locations of lipids in biological tissues. However, a major challenge in interpreting the biological significance of local lipid compositions and distributions detected using MALDI-MSI is the difficulty in associating spectra with cellular lipid metabolism within the tissue. By-and-large this is due to the typically limited spatial resolution of MALDI-MSI (30-100 μm) meaning individual spectra represent the average spectrum acquired from multiple adjacent cells, each potentially possessing a unique lipid composition and biological function. The use of oversampling is one promising approach to decrease the sampling area and improve the spatial resolution in MALDI-MSI, but it can suffer from a dramatically decreased sensitivity. In this work we overcome these challenges through the coupling of oversampling MALDI-MSI with laser post-ionisation (MALDI-2). We demonstrate the ability to acquire rich lipid spectra from pixels as small as 6 μm, equivalent to or smaller than the size of typical mammalian cells. Coupled with an approach for automated lipid identification, it is shown that MALDI-2 combined with oversampling at 6 μm pixel size can detect up to three times more lipids and many more lipid classes than even conventional MALDI at 20 μm resolution in the positive-ion mode. Applying this to mouse kidney and human brain tissue containing active multiple sclerosis lesions, where 74 and 147 unique lipids are identified, respectively, the localisation of lipid signals to individual tubuli within the kidney and lipid droplets with lesion-specific macrophages is demonstrated.

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“…As part of the host response against infection, lipid responses receive increasing attention in the scientific community ( 51 ). Little is known about how exogenous PEA can modulate other lipid mediators involved in neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

“…No data are available during infection. Here, we used targeted quantification of lipids to evaluate whether PEA could modify the levels of several bioactive lipids ( 51 ). In the systemic circulation, prophylactic PEA significantly reduced concentrations of two pro-inflammatory mediators: AA and one of its metabolites, 20-HETE which unveils a novel anti-inflammatory mode of action of PEA during infection.…”

Section: Discussionmentioning

confidence: 99%

Prophylactic Palmitoylethanolamide Prolongs Survival and Decreases Detrimental Inflammation in Aged Mice With Bacterial Meningitis

et al. 2018

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Easy-to-achieve interventions to promote healthy longevity are desired to diminish the incidence and severity of infections, as well as associated disability upon recovery. The dietary supplement palmitoylethanolamide (PEA) exerts anti-inflammatory and neuroprotective properties. Here, we investigated the effect of prophylactic PEA on the early immune response, clinical course, and survival of old mice after intracerebral E. coli K1 infection. Nineteen-month-old wild type mice were treated intraperitoneally with two doses of either 0.1 mg PEA/kg in 250 μl vehicle solution (n = 19) or with 250 μl vehicle solution only as controls (n = 19), 12 h and 30 min prior to intracerebral E. coli K1 infection. The intraperitoneal route was chosen to reduce distress in mice and to ensure exact dosing. Survival time, bacterial loads in cerebellum, blood, spleen, liver, and microglia counts and activation scores in the brain were evaluated. We measured the levels of IL-1β, IL-6, MIP-1α, and CXCL1 in cerebellum and spleen, as well as of bioactive lipids in serum in PEA- and vehicle-treated animals 24 h after infection. In the absence of antibiotic therapy, the median survival time of PEA-pre-treated infected mice was prolonged by 18 h compared to mice of the vehicle-pre-treated infected group (P = 0.031). PEA prophylaxis delayed the onset of clinical symptoms (P = 0.037). This protective effect was associated with lower bacterial loads in the spleen, liver, and blood compared to those of vehicle-injected animals (P ≤ 0.037). PEA-pre-treated animals showed diminished levels of pro-inflammatory cytokines and chemokines in spleen 24 h after infection, as well as reduced serum concentrations of arachidonic acid and of one of its metabolites, 20-hydroxyeicosatetraenoic acid. In the brain, prophylactic PEA tended to reduce bacterial titers and attenuated microglial activation in aged infected animals (P = 0.042). Our findings suggest that prophylactic PEA can counteract infection associated detrimental responses in old animals. Accordingly, PEA treatment slowed the onset of infection symptoms and prolonged the survival of old infected mice. In a clinical setting, prophylactic administration of PEA might extend the potential therapeutic window where antibiotic therapy can be initiated to rescue elderly patients.

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Host-based lipid inflammation drives pathogenesis in Francisella infection

Cited by 37 publications

References 53 publications

Maintenance of Deep Lung Architecture and Automated Airway Segmentation for 3D Mass Spectrometry Imaging

Maintenance of Deep Lung Architecture and Automated Airway Segmentation for 3D Mass Spectrometry Imaging

Evaluation of lipid coverage and high spatial resolution MALDI-imaging capabilities of oversampling combined with laser post-ionisation

Prophylactic Palmitoylethanolamide Prolongs Survival and Decreases Detrimental Inflammation in Aged Mice With Bacterial Meningitis

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