Lysosomal Lipases PLRP2 and LPLA2 Process Mycobacterial Multi-acylated Lipids and Generate T Cell Stimulatory Antigens

Gilleron, Martine; Lepore, Marco; Layre, Emilie; Paepe, Diane Cala‐De; Mebarek, Naila; Shayman, James A.; Canaan, Stéphane; Mori, Lucia; Carrière, Frédéric; Puzo, Germain; Libero, Gennaro De

doi:10.1016/j.chembiol.2016.07.021

Cited by 31 publications

(22 citation statements)

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“…This enzyme participates in the cytotoxic activity of T-cells in mice [ 59 ]. By removing fatty acids, human PLRP2 process lipid antigens have a role in T cell immunity against mycobacteria [ 60 ]. Cellular TPA (see structure in [ 54 ]) uptake is largely based on partitioning of this lipophilic substance into the lipid phase of the cell membranes [ 61 ].…”

Section: Resultsmentioning

confidence: 99%

Functional characterization of the Hyles euphorbiae hawkmoth transcriptome reveals strong expression of phorbol ester detoxification and seasonal cold hardiness genes

et al. 2018

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BackgroundThe European spurge hawkmoth, Hyles euphorbiae (Lepidoptera, Sphingidae), has been intensively studied as a model organism for insect chemical ecology, cold hardiness and evolution of species delineation. To understand species isolation mechanisms at a molecular level, this study aims at determining genetic factors underlying two adaptive ecological trait candidates, phorbol ester (TPA) detoxification and seasonal cold acclimation.MethodA draft transcriptome of H. euphorbiae was generated using Illumina sequencing, providing the first genomic resource for the hawkmoth subfamily Macroglossinae. RNA expression levels in tissues of experimental TPA feeding larvae and cooled pupae was compared to levels in control larvae and pupae using 26 bp RNA sequence tag libraries (DeepSuperSAGE). Differential gene expression was assessed by homology searches of the tags in the transcriptome.ResultsIn total, 389 and 605 differentially expressed transcripts for detoxification and cold hardiness, respectively, could be identified and annotated with proteins. The majority (22 of 28) of differentially expressed detox transcripts of the four ‘drug metabolism’ enzyme groups (cytochrome P450 (CYP), carboxylesterases (CES), glutathione S-transferases (GST) and lipases) are up-regulated. Triacylglycerol lipase was significantly over proportionally annotated among up-regulated detox transcripts. We record several up-regulated lipases, GSTe2, two CESs, CYP9A21, CYP6BD6 and CYP9A17 as candidate genes for further H. euphorbiae TPA detoxification analyses. Differential gene expression of the cold acclimation treatment is marked by metabolic depression with enriched Gene Ontology terms among down-regulated transcripts almost exclusively comprising metabolism, aerobic respiration and dissimilative functions. Down-regulated transcripts include energy expensive respiratory proteins like NADH dehydrogenase, cytochrome oxidase and ATP synthase. Gene expression patterns show shifts in carbohydrate metabolism towards cryoprotectant production. The Glycolysis enzymes, G1Pase, A1e, Gpi and an Akr isoform are up-regulated. Glycerol, an osmolyte which lowers the body liquid supercooling point, appears to be the predominant polyol cryoprotectant in H. euphorbiae diapause pupae. Several protein candidates involved in glucose, glycerol, myo-inositol and potentially sorbitol and trehalose synthesis were identified. ConclusionsA majority of differently expressed transcripts unique for either detoxification or cold hardiness indicates highly specialized functional adaptation which may have evolved from general cell metabolism and stress response.The transcriptome and extracted candidate biomarkers provide a basis for further gene expression studies of physiological processes and adaptive traits in H. euphorbiae.Electronic supplementary materialThe online version of this article (10.1186/s12983-018-0252-2) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Functional characterization of the Hyles euphorbiae hawkmoth transcriptome reveals strong expression of phorbol ester detoxification and seasonal cold hardiness genes

et al. 2018

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“…This interesting finding suggests either a difference in the type of PIM produced by the bacteria located within the neutrophil-rich region or differential host-cell processing of bacterial lipids within different granuloma-cell types. 34 , 35 …”

Section: Results and Discussionmentioning

confidence: 99%

Visualization of Mycobacterial Biomarkers and Tuberculosis Drugs in Infected Tissue by MALDI-MS Imaging

et al. 2018

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MALDI mass-spectrometry imaging (MALDI-MSI) is a technique capable of the label-free identification and visualization of analytes in tissue sections. We have previously applied MALDI-MSI to the study of the spatial distribution of tuberculosis (TB) drugs in necrotic lung granulomas characteristic of pulmonary TB disease, revealing heterogeneous and often suboptimal drug distributions. To investigate the impact of differential drug distributions at sites of infection, we sought to image mycobacterial biomarkers to coregister drugs and bacteria in lesion sections. The traditional method of visualizing Mycobacterium tuberculosis inside lesions is acid-fast staining and microscopy. Directly analyzing and visualizing mycobacteria-specific lipid markers by MALDI-MSI provides detailed molecular information on bacterial distributions within granulomas, complementary to high-spatial-resolution staining and microscopy approaches. Moreover, spatial monitoring of molecular changes occurring in bacteria during granuloma development can potentially contribute to a greater understanding of pulmonary-TB pathogenesis. In this study, we developed a MALDI-MSI method to detect and visualize specific glycolipids of mycobacteria within TB lesions. The biomarker signal correlated well with the bacteria visualized by IHC and acid-fast staining. This observation was seen in samples collected from multiple animal models. Although individual bacteria could not be visualized because of the limit of spatial resolution (50 μm), bacterial clusters were clearly detected and heterogeneously distributed throughout lesions. The ability to visualize drugs, metabolites, and bacterial biomarkers by MALDI-MSI enabled direct colocalization of drugs with specific bacterial target populations (identifiable by distinct metabolic markers). Future applications include assessing drug activity in lesions by visualizing drug-mediated lipid changes and other drug-induced mycobacterial metabolic responses.

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“…Generally, each of them preferentially binds one of the four CD1 isoforms equipped with antigen presentation capacity (CD1a, b, c, and d), although promiscuity is also observed ( 4 , 12 , 14 , 17 , 24 , 26 , 28 – 30 ). Several factors such as the unique variations in the architecture of individual CD1 isoforms, their diverse intracellular trafficking routes, their differential pH requirements for optimal loading and their co-localization with distinct lipid-remodeling enzymes and chaperon proteins, dictate the type and the size of lipid antigens they present to T cells ( 13 , 31 – 34 ).…”

Section: Adaptive-like T Cells Restricted To Cd1mentioning

confidence: 99%

The Conventional Nature of Non-MHC-Restricted T Cells

2018

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The definition “unconventional T cells” identifies T lymphocytes that recognize non-peptide antigens presented by monomorphic antigen-presenting molecules. Two cell populations recognize lipid antigens and small metabolites presented by CD1 and MR1 molecules, respectively. A third cell population expressing the TCR Vγ9Vδ2 is stimulated by small phosphorylated metabolites. In the recent past, we have learnt a lot about the selection, tissue distribution, gene transcription programs, mode of expansion after antigen recognition, and persistence of these cells. These studies depict their functions in immune homeostasis and diseases. Current investigations are revealing that unconventional T cells include distinct sub-populations, which display unexpected similarities to classical MHC-restricted T cells in terms of TCR repertoire diversity, antigen specificity variety, functional heterogeneity, and naïve-to-memory differentiation dynamic. This review discusses the latest findings with a particular emphasis on these T cells, which appear to be more conventional than previously appreciated, and with the perspective of using CD1 and MR1-restricted T cells in vaccination and immunotherapy.

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Lysosomal Lipases PLRP2 and LPLA2 Process Mycobacterial Multi-acylated Lipids and Generate T Cell Stimulatory Antigens

Cited by 31 publications

References 51 publications

Functional characterization of the Hyles euphorbiae hawkmoth transcriptome reveals strong expression of phorbol ester detoxification and seasonal cold hardiness genes

Functional characterization of the Hyles euphorbiae hawkmoth transcriptome reveals strong expression of phorbol ester detoxification and seasonal cold hardiness genes

Visualization of Mycobacterial Biomarkers and Tuberculosis Drugs in Infected Tissue by MALDI-MS Imaging

The Conventional Nature of Non-MHC-Restricted T Cells

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